Macrocyclic indoles as hepatitis C virus inhibitors

ABSTRACT

The present invention relates to inhibitors of HCV replication of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts, the quaternary amines and the stereochemically isomeric forms thereof, 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 ; R 3 ; and R 4  have the meaning defined in the claims. 
           
         
       
    
     The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.

This application is a divisional application of U.S. application Ser.No. 12/809,160, filed Jun. 18, 2010, which is a national stageapplication of PCT/EP2008/068280, filed Dec. 23, 2008, which claimspriority benefit of Application No. EP07150415.3 filed Dec. 24, 2007.The complete disclosures of the aforementioned related patentapplications are hereby incorporated herein by reference for allpurposes.

FIELD OF THE INVENTION

The present invention is concerned with macrocyclic indoles havinginhibitory activity on the replication of the hepatitis C virus (HCV).It further concerns compositions comprising these compounds as activeingredients as well as processes for preparing these compounds andcompositions.

BACKGROUND OF THE INVENTION

Hepatitis C virus is the leading cause of chronic liver diseaseworldwide and has become a focus of considerable medical research. HCVis a member of the Flaviviridae family of viruses in the hepacivirusgenus, and is closely related to the flavivirus genus, which includes anumber of viruses implicated in human disease, such as dengue virus andyellow fever virus, and to the animal pestivirus family, which includesbovine viral diarrhoea virus (BVDV). HCV is a positive-sense,single-stranded RNA virus, with a genome of around 9,600 bases. Thegenome comprises both 5′ and 3′ untranslated regions which adopt RNAsecondary structures, and a central open reading frame that encodes asingle polyprotein of around 3,010-3,030 amino acids. The polyproteinencodes ten gene products which are generated from the precursorpolyprotein by an orchestrated series of co- and posttranslationalendoproteolytic cleavages mediated by both host and viral proteases. Theviral structural proteins include the core nucleocapsid protein, and twoenvelope glycoproteins E1 and E2. The non-structural (NS) proteinsencode some essential viral enzymatic functions (helicase, polymerase,protease), as well as proteins of unknown function. Replication of theviral genome is mediated by an RNA-dependent RNA polymerase, encoded bynon-structural protein 5b (NS5B). In addition to the polymerase, theviral helicase and protease functions, both encoded in the bifunctionalNS3 protein, have been shown to be essential for replication of HCV RNA.HCV also encodes a metalloproteinase in the NS2 region.

HCV replicates preferentially in hepatocytes but is not directlycytopathic, leading to persistent infection. In particular, the lack ofa vigorous T-lymphocyte response and the high propensity of the virus tomutate appear to promote a high rate of chronic infection. There are 6major HCV genotypes and more than 50 subtypes, which are differentlydistributed geographically. HCV type 1 is the predominant genotype inthe US and Europe. For instance, HCV type 1 accounts for 70 to 75percent of all HCV infections in the United States. The extensivegenetic heterogeneity of HCV has important diagnostic and clinicalimplications, perhaps explaining difficulties in vaccine development andthe lack of response to therapy. An estimated 170 million personsworldwide are infected with hepatitis C virus (HCV). Following theinitial acute infection, a majority of infected individuals developchronic hepatitis, which can progress to liver fibrosis leading tocirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma)(National Institutes of Health Consensus Development ConferenceStatement: Management of Hepatitis C. Hepatology, 36, 5 Suppl. S3-S20,2002). Liver cirrhosis due to HCV infection is responsible for about10,000 deaths per year in the U.S.A. alone, and is the leading cause forliver transplantations. Transmission of HCV can occur through contactwith contaminated blood or blood products, for example following bloodtransfusion or intravenous drug use. The introduction of diagnostictests used in blood screening has led to a downward trend inpost-transfusion HCV incidence. However, given the slow progression tothe end-stage liver disease, the existing infections will continue topresent a serious medical and economic burden for decades (Kim, W. R.Hepatology, 36, 5 Suppl. S30-S34, 2002).

Current HCV therapies are based on (pegylated) interferon-alpha (IFN-α)in combination with ribavirin. This combination therapy yields asustained virologic response in more than 40% of patients infected bygenotype 1 viruses and about 80% of those infected by genotypes 2 and 3.Beside the limited efficacy on HCV type 1, combination therapy hassignificant side effects and is poorly tolerated in many patients. Forinstance, in registration trials of pegylated interferon and ribavirin,significant side effects resulted in discontinuation of treatment inapproximately 10 to 14 percent of patients. Major side effects ofcombination therapy include influenza-like symptoms, hematologicabnormalities, and neuropsychiatric symptoms. The development of moreeffective, convenient and tolerated treatments is a major public healthobjective. Thus, the treatment of this chronic disease is an unmetclinical need, since current therapy is only partially effective andlimited by undesirable side effects.

One area of particular focus has been the search for inhibitors of theNS5b RNA-dependent RNA polymerase. Close structural homologs of thispolymerase do not exist within the uninfected host cell and the findingof inhibitors of said polymerase would provide a more specific mode ofaction Inhibitors which are currently under investigation can beclassified as either nucleoside inhibitors (NIs) or non-nucleosideinhibitors (NNIs). NIs directly compete with nucleotide substrates forbinding to highly conserved active sites. Greater specificity may beachieved by NNIs, which interact outside of the highly conserved activesite at a unique allosteric site common only to structurally relatedpolymerases. Preliminary clinical trials have resulted in a high failurerate, thereby highlighting the need to pursue the search for novel NS5binhibitors.

SUMMARY OF THE INVENTION

It has been found that certain macrocyclic indole derivatives exhibitantiviral activity in mammals infected with HCV. These compounds aretherefore useful in treating or combating HCV infections.

The present invention concerns inhibitors of HCV replication, which canbe represented by formula (I):

and the stereoisomers, tautomers, racemics, salts, hydrates or solvatesthereof, wherein R¹ is a bivalent chain selected from

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents isattached to the remainder of the molecule via the nitrogen atom of theamide group, and the carbon atom of the acetamide moiety is attached tothe remainder of the molecule via the nitrogen of the indole ring of thecompound of formula (I); or

-   R¹ is a bivalent chain selected from

wherein the sulfonyl group is attached to the remainder of the moleculevia the nitrogen atom of the amide group, and the carbon atom of theacetamide moiety is attached to the remainder of the molecule via thenitrogen of the indole ring of the compound of formula (I);

-   X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;-   each of a, b, c, d, e, f, g, and h, is, independently, an integer    selected from 0, 1, 2, 3, 4, or 5, with the proviso that the    macrocycle formed by the bivalent chain R¹, the —C(═O)—NH— moiety to    which R¹ is attached and the nitrogen and carbon atoms N1, C6, C7,    and C7′ of the indole ring, has from 14 to 17 member atoms;-   each parallel dashed line (represented by    ) represents an optional double bond;-   R² is hydrogen or C₁₋₆alkyl;-   R³ is C₃₋₇cycloalkyl;-   R⁴ is a group selected from:

-   R^(5s) and R^(5b) are each independently selected from hydrogen;    C₁₋₆alkyl; or haloC₁₋₆alkyl;-   n is 0, 1, or 2;-   R⁶ is selected from hydrogen, halo, C₁₋₆alkyl, or C₃₋₇cycloalkyl;-   R^(6a) is selected from hydrogen, halo, C₁₋₆alkyl, or    C₃₋₇cycloalkyl;-   R⁷ is phenyl or thiazolyl, wherein each phenyl is optionally    substituted with one, two, or three substituents, wherein each    thiazolyl is optionally substituted with one or two substituents;    wherein the substituents on both phenyl and thiazolyl are each    independently selected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²;    —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b);    —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹;    —SO₂NR^(9a)R^(9b); phenyl optionally substituted with one, two or    three substituents each independently selected from halo,    trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and    —C(═O)NR^(9a)R^(9b); and Het optionally substituted with one or two    substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   R⁸ is hydrogen, phenyl, or thiazolyl, wherein each phenyl is    optionally substituted with one, two, or three substituents, wherein    each thiazolyl is optionally substituted with one or two    substituents; wherein the substituents on both phenyl and thiazolyl    are each independently selected from halo; cyano; nitro; C₁₋₆alkyl;    —OR¹²; —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b);    —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹;    —SO₂NR^(9a)R^(9b); phenyl optionally substituted with one, two or    three substituents each independently selected from halo,    trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and    —C(═O)NR^(9a)R^(9b); and Het optionally substituted with one or two    substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁ _(_) ₆alkyl;-   R^(9a) and R^(9b) are each independently selected from hydrogen,    C₁₋₆alkyl, or arylC₁₋₆alkyl; or R^(9a) and R^(9b), together with the    nitrogen to which they are attached, form a saturated, partially    unsaturated, or completely unsaturated 5-8 membered monocycle,    wherein said monocycle optionally contains one additional heteroatom    selected from the group consisting of oxygen, sulfur and nitrogen,    and wherein the remaining monocycle members are carbon atoms;    wherein said monocycle is optionally substituted on any carbon atom    with one or two substituents each independently selected from halo,    C₁₋₆alkyl, hydroxy, or oxo, wherein aryl is phenyl or naphthyl;-   R¹⁰ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R¹¹ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R¹² is hydrogen, C₁₋₆alkyl, or benzyl;-   R¹³ is C₁₋₆alkyl;-   Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

In one embodiment, the invention concerns as subgroup of the compoundsof formula (I), said subgroup hereinafter designated as compounds offormula (I′), wherein the compounds of formula (I′) are those compoundsof formula (I) and the stereoisomers, tautomers, racemics, salts,hydrates or solvates thereof, wherein

-   R¹ is a bivalent chain selected from

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents (theleft side of the depicted R¹ chains) is attached to the remainder of themolecule via the nitrogen atom of the amide group, and the carbon atomof the acetamide moiety (the right side of the depicted R¹ chains) isattached to the remainder of the molecule via the nitrogen of the indolering of the compound of formula (I);each parallel dashed line (represented by

) represents an optional double bond;

-   R⁴ is a group selected from:

-   X, a, b, c, d, e, f, g, h, R², R³, R^(5a), R^(5b), n, R⁶, R⁷, R⁸,    R^(9a), R^(9b), R¹⁰, R¹¹, R¹², R¹³ and Het have the same meanings as    defined above.

The invention further relates to methods for the preparation of thecompounds of formula (I) or any subgroup thereof, the N-oxides,quaternary amines, metal complexes, and stereochemically isomeric formsthereof, their intermediates, and the use of the intermediates in thepreparation of the compounds of formula (I).

The invention relates to the compounds of formula (I) per se or anysubgroup thereof, the N-oxides, salts, quaternary amines, metalcomplexes, and stereochemically isomeric forms thereof, for use as amedicament. The invention relates to the compounds of formula (I) per seor any subgroup thereof, the N-oxides, salts, quaternary amines, metalcomplexes, and stereochemically isomeric forms thereof, for treatinghepatitis C. The invention further relates to pharmaceuticalcompositions comprising a carrier and an anti-virally effective amountof a compound of formula (I) or any subgroup thereof as specifiedherein. The pharmaceutical compositions may comprise combinations of theaforementioned compounds with other anti-HCV agents. The pharmaceuticalcompositions may comprise combinations of the aforementioned compoundswith anti-HIV agents. The invention further relates to theaforementioned pharmaceutical compositions for administration to asubject suffering from HCV infection.

The invention also relates to the use of a compound of formula (I) orany subgroup thereof, or an N-oxide, salt, quaternary amine, metalcomplex, or stereochemically isomeric forms thereof, for the manufactureof a medicament for inhibiting HCV replication. Or the invention relatesto a method of inhibiting HCV replication in a warm-blooded animal saidmethod comprising the administration of an effective amount of acompound of formula (I) or any subgroup thereof, or an N-oxide, salt,quaternary amine, metal complex, or stereochemically isomeric formsthereof.

DETAILED DESCRIPTION

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.Each aspect so defined may be combined with any other aspect or aspectsunless clearly indicated to the contrary. In particular, any featureindicated as being preferred or advantageous may be combined with anyother feature or features indicated as being preferred or advantageous.

In a particular embodiment, the present invention provides a compound offormula (I) or (I′) having one of the structural Formula (II), (III), or(IV), or a stereoisomer, tautomer, racemic, metabolite, salt, hydrate,or solvate thereof,

wherein R¹, R³, R⁶, R⁷, R⁸ and n have the same meaning as that definedabove.

Another particular embodiment of the present invention relates to acompound of formula (I) having the structural Formula (V), or astereoisomer, tautomer, racemic, metabolite, salt, hydrate, or solvatethereof,

wherein R¹, R³, R⁶ and R^(6a) have the same meaning as that definedabove.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless thecontext dictates otherwise.

Whenever the term “substituted” is used in the present invention, it ismeant to indicate that one or more hydrogens on the atom indicated inthe expression using “substituted” is replaced with a selection from theindicated group, provided that the indicated atom's normal valency isnot exceeded, and that the substitution results in a chemically stablecompound, i.e. a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into a therapeutic agent.

The term halo is generic to fluoro, chloro, bromo and iodo.

As used herein “C₁₋₄alkyl” as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 4 carbon atoms such as for example methyl, ethyl, prop-1-yl,prop-2-yl, but-1-yl, but-2-yl, isobutyl, 2-methyl-prop-1-yl; “C₁₋₆alkyl”encompasses C₁₋₄alkyl radicals and the higher homologues thereof having5 or 6 carbon atoms such as, for example, pent-1-yl, pent-2-yl,pent-3-yl, hex-1-yl, hex-2-yl, 2-methyl-but-1-yl, 2-methyl-pent-1-yl,2-ethyl-but-1-yl, 3-methyl-pent-2-yl, and the like. Of interest amongstC₁₋₆alkyl is C₁₋₄alkyl.

The term “haloC₁₋₆alkyl” alone or in combination, refers to a C₁₋₆alkylradical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen as defined above. Non-limitingexamples of such haloC₁₋₆alkyl radicals include chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and1,1,1-trifluoroethyl.

The term “C₃₋₇cycloalkyl as used herein is a cyclic alkyl group, that isto say, a monovalent, saturated, or unsaturated hydrocarbyl group.C₃₋₇cycloalkyl groups may comprise 3 or more carbon atoms in the ringand generally, according to this invention comprise from 3 to 7, morepreferably from 3 to 6 carbons. Examples of C₃₋₇cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

The term “C₁₋₆alkoxy” or “C₁₋₆alkyloxy” as used herein refers to aradical having the Formula —OR^(a) wherein R^(a) is C₁₋₆alkyl as definedabove. Non-limiting examples of suitable C₁₋₆alkoxy include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentyloxy and hexyloxy. Suitable C₁₋₄alkoxy include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term “aryl” as a group or part of a group is meant to includephenyl, naphth-1-yl, or naphth-2-yl.

As used herein before, the term (═O) or oxo forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom. Whenever a ring or ring system is substituted with an oxogroup, the carbon atom to which the oxo is linked is a saturated carbon.

The term “C₁₋₆alkylsulfonyl” alone or in combination refers to a groupof Formula —SO₂—R^(b) wherein R^(b) is C₁₋₆alkyl as defined herein.Non-limiting examples of C₁₋₆alkylsulfonyl groups includemethylsulfonyl, ethylsulfonyl, butylsulfonyl, n-propylsulfonyl,n-pentylsulfonyl, and hexylsulfonyl.

It should be noted that the radical positions on any molecular moietyused in the definitions may be anywhere on such moiety as long as it ischemically stable.

Radicals used in the definitions of the variables include all possibleisomers unless otherwise indicated. For instance, piperidinyl includespiperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl;pentyl includes pent-1-yl, pent-2-yl and pent-3-yl.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

As used in the specification and the appended claims, the singular forms“a”, “an,” and “the” include plural referents unless the context clearlydictates otherwise. By way of example, “a compound” means one compoundor more than one compound.

Whenever used hereinafter, the term “compounds of formula (I)”, “thepresent compounds” or “the compounds of formula (I) or any subgroupthereof” or similar terms, it is meant to include the compounds offormula (I) and any subgroup thereof, their N-oxides, salts, quaternaryamines, metal complexes, solvates, hydrates, and stereochemicallyisomeric forms. One embodiment comprises the compounds of formula (I) orany subgroup of compounds of formula (I) specified herein, as well asthe N-oxides, salts, as the possible stereoisomeric forms thereof.Another embodiment comprises the compounds of formula (I) or anysubgroup of compounds of formula (I) specified herein, as well as thesalts as the possible stereoisomeric forms thereof.

The compounds of formula (I) and any subgroup thereof may have severalcenters of chirality and may exist as stereochemically isomeric forms.The term “stereochemically isomeric forms” as used herein defines allthe possible compounds made up of the same atoms bonded by the samesequence of bonds but having different three-dimensional structures,which the compounds of formula (I) may possess.

With reference to the instances where (R) or (S) is used to designatethe absolute configuration of a chiral atom within a substituent, thedesignation is done taking into consideration the whole compound and notthe substituent in isolation.

Unless otherwise mentioned or indicated, the chemical designation of acompound encompasses the mixture of all possible stereochemicallyisomeric forms, which said compound may possess. Said mixture maycontain all diastereomers and/or enantiomers of the basic molecularstructure of said compound. All stereochemically isomeric forms of thecompounds of the present invention both in pure form or mixed with eachother are intended to be embraced within the scope of the presentinvention.

Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term“stereoisomerically pure” concerns compounds or intermediates having astereoisomeric excess of at least 80% (i.e. minimum 90% of one isomerand maximum 10% of the other possible isomers) up to a stereoisomericexcess of 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms “enantiomerically pure” and“diastereomerically pure” should be understood in a similar way, butthen having regard to the enantiomeric excess, and the diastereomericexcess, respectively, of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The diastereomeric racemates of the compounds of formula (I) can beobtained separately by conventional methods. Appropriate physicalseparation methods that may advantageously be employed are, for example,selective crystallization and chromatography, e.g. columnchromatography.

For some of the compounds of formula (I), their N-oxides, salts,quaternary amines, or metal complexes, and the intermediates used in thepreparation thereof, the absolute stereochemical configuration was notexperimentally determined. A person skilled in the art is able todetermine the absolute configuration of such compounds using art-knownmethods such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atomsoccurring on the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counter-ion is pharmaceutically acceptable. However, saltsof acids and bases which are non-pharmaceutically acceptable may alsofind use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid and base addition salt forms which the compounds of formula (I) areable to form. The pharmaceutically acceptable acid addition salts canconveniently be obtained by treating the base form with such appropriateacid. Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.

Conversely, said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several nitrogen atoms areoxidized to the so-called N-oxide.

It will be appreciated that the compounds of formula (I) may have metalbinding, chelating, complex forming properties and therefore may existas metal complexes or metal chelates. Such metalated derivatives of thecompounds of formula (I) are intended to be included within the scope ofthe present invention.

Some of the compounds of formula (I) or any subgroup thereof may alsoexist in their tautomeric form. Such forms although not explicitlyindicated in the above formula are intended to be included within thescope of the present invention.

An embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV) or of any subgroup thereof, wherein one or moreof the following restrictions apply:

-   (a) R¹ is the bivalent chain selected from the group consisting of

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents isattached to the remainder of the molecule via the nitrogen atom of theamide group, and the carbon atom of the acetamide moiety is attached tothe remainder of the molecule via the nitrogen atom of the indole ringof the compound of formula (I);

-   (b) each of a, b, c, d, e, f, g, and h is, independently, 0, 1, 2,    or 3, with the proviso that the macrocycle formed by the bivalent    chain R¹, the —C(═O)—NH— moiety to which R¹ is attached and the    nitrogen and carbon atoms N1, C6, C7, and C7′ of the indole ring,    has from 14 to 17 member atoms;-   (c) each parallel dashed line (represented by    ) represents an optional double bond;-   (d) R² is hydrogen or C₁₋₄alkyl;-   (e) R³ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;-   (f) X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;

(g) R^(5a) and R^(5b) are each independently selected from hydrogen;C₁₋₄alkyl; haloC₁₋₄alkyl;

-   (h) R⁶ is hydrogen, C₁₋₆alkyl, or fluoro;-   (i) n is 1, or 2;-   (j) R² is phenyl or thiazolyl, wherein each phenyl is optionally    substituted with one, two, or three substituents, wherein each    thiazolyl is optionally substituted with one or two substituents;    wherein the substituents on both phenyl and thiazolyl are each    independently selected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²;    —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b);    —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹;    —SO₂NR^(9a)R^(9b); phenyl optionally substituted with one, two or    three substituents each independently selected from halo,    trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and    —C(═O)NR^(9a)R^(9b); and Het optionally substituted with one or two    substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   (k) R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one, two, or three substituents each independently    selected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²;    —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³;    —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b);    phenyl optionally substituted with one, two or three substituents    each independently selected from halo, trifluoromethyl, cyano,    C₁₋₆alkyl, C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally    substituted with one or two substituents each independently selected    from oxo, C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   (l) R^(9a) and R^(9b) are each independently selected from hydrogen,    C₁₋₆alkyl, or arylC₁₋₆alkyl; or R^(9a) and R^(9b), together with the    nitrogen to which they are attached, form a saturated, partially    unsaturated, or completely unsaturated 5-8 membered monocycle,    wherein said monocycle optionally contains one additional heteroatom    selected from the group consisting of oxygen, sulfur and nitrogen,    and wherein the remaining monocycle members are carbon atoms;    wherein said monocycle is optionally substituted on any carbon atom    with one or two substituents each independently selected from halo,    C₁₋₆alkyl, hydroxy, or oxo;-   (m) R¹⁰ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   (n) R¹¹ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   (o) R¹² is hydrogen or C₁₋₆alkyl;-   (p) R¹³ is C₁₋₆alkyl;-   (q) Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

One embodiment of the present invention concerns compounds of formula(I), (II),

(III), (IV) or of any subgroup thereof, wherein one or more of thefollowing restrictions apply:

-   (a) R¹ is the bivalent chain selected from the group consisting of

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents isattached to the remainder of the molecule via the nitrogen atom of theamide group, and the carbon atom of the acetamide moiety is attached tothe remainder of the molecule via the nitrogen atom of the indole ringof the compound of formula (I);

-   (b) each of a, b, c, d, e, f, g, and h is, independently, 0 1, 2, or    3, with the proviso that the macrocycle formed by the bivalent chain    R¹, the —C(═O)—NH— moiety to which R¹ is attached and the nitrogen    and carbon atoms N1, C6, C7, and C7′ of the indole ring, has from 14    to 16 member atoms;-   (c) each parallel dashed line (represented by    ) represents an optional double bond;-   (d) R² is hydrogen or C₁₋₄alkyl;-   (e) R³ is cyclopentyl or cyclohexyl;-   (f) X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;-   (g) R^(5a) and R^(5b) are each independently selected from hydrogen;    C₁₋₃alkyl; haloC₁₋₃alkyl;-   (h) R⁶ is hydrogen, C₁₋₆alkyl, or fluoro;-   (i) n is 1, or 2;-   (j) R⁷ is phenyl or thiazolyl, wherein said phenyl and thiazolyl are    each independently optionally substituted with one, two or three    substituents each independently selected from halo; cyano; nitro;    C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b);    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b);    —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b); phenyl optionally substituted    with one or two substituents each independently selected from halo,    trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and    —C(═O)NR^(9a)R^(9b); and Het optionally substituted with one or two    substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   (k) R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one or two substituents each independently selected    from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³;    —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; phenyl    optionally substituted with one or two substituents each    independently selected from halo, trifluoromethyl, cyano, C₁₋₆alkyl,    C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally substituted    with one or two substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   (l) R^(9a) and R^(9b) are each independently selected from hydrogen    or C₁₋₆alkyl;-   (m) R¹² is hydrogen or C₁₋₆alkyl;-   (n) R¹³ is C₁₋₆alkyl;-   (o) Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

One embodiment of the present invention concerns compounds of formula(I), (I), (II), (III), (IV) or of any subgroup thereof, wherein one ormore of the following restrictions apply:

-   (a) R¹ is the bivalent chain selected from the group consisting of

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents isattached to the remainder of the molecule via the nitrogen atom of theamide group, and the carbon atom of the acetamide moiety is attached tothe remainder of the molecule via the nitrogen atom of the indole ringof the compound of formula (I);

-   (b) each of a, b, c, d, e, f, g, and h is, independently, 0, 1, 2,    or 3, with the proviso that the macrocycle formed by the bivalent    chain R¹, the —C(═O)—NH— moiety to which R¹ is attached and the    nitrogen and carbon atoms N1, C6, C7, and C7′ of the indole ring,    has from 14 to 16 member atoms;-   (c) each parallel dashed line (represented by    ) represents an optional double bond;-   (d) R² is hydrogen;-   (e) R³ is cyclohexyl;-   (f) X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;-   (g) R^(5a) and R^(5b) are each independently selected from hydrogen;    C₁₋₂alkyl; trifluoromethyl;-   (h) R⁶ is hydrogen or fluoro;-   (i) n is 1;-   (j) R⁷ is phenyl or thiazolyl, wherein said phenyl and thiazolyl are    each independently optionally substituted with one or two    substituents each independently selected from halo; nitro;    C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b);    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b);    phenyl optionally substituted with one or two substituents each    independently selected from halo, trifluoromethyl, C₁₋₆alkyl, and    C₁₋₆alkoxy; and Het optionally substituted with C₁₋₆alkylsulfonyl;-   (k) R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one or two substituents each independently selected    from halo; nitro; —OR¹²; —C(═O)OR¹²; —C(═O)NR^(9a)R^(9b);    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; phenyl optionally substituted with    halo; and Het optionally substituted with one or two substituents    each independently selected from oxo or C₁₋₆alkylsulfonyl;-   (l) R^(9a) and R^(9b) are each independently selected from hydrogen    or C₁₋₆alkyl;-   (m) R¹² is hydrogen or C₁₋₆alkyl;-   (n) R¹³ is C₁₋₆alkyl;-   (o) Het is pyrrolidinyl, morpholinyl, or piperazinyl.

One embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV) or of any subgroup thereof, wherein R^(9a) andR^(9b), together with the nitrogen to which they are attached, form amorpholin-4-yl, 2-oxo-pyrrolidinyl, pyrrolidinyl, piperidinyl, orpiperazinyl.

One embodiment of the present invention concerns compounds of formula(I), (I), (II), (III), (IV) or of any subgroup thereof, wherein a is 0or 1, b is 1 or 2, g is 0 or 1, and h is 1 or 2:

One embodiment of the present invention concerns compounds of formula(I), (I), (II), (III), (IV) or of any subgroup thereof, wherein a is 1,b is 2, g is 0 or 1, and h is 1 or 2:

Particular subgroups of compounds of formula (I), (II), (III), or (IV)are those represented by the following structural formulae (II-a),(III-a), (IV-a), (II-b), (III-b), (IV-b) such as for example (II-aa),(III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb), (II-bbb), (III-bbb),(IV-bbb),

wherein the parallel dashed line, a, b, g, h, R³, R^(5a), R^(5b), R⁶,R⁷, X, n, and R⁸, where appropriate, have the same meaning as thatdefined above or in any of the subgroups of compounds of formula (I)specified herein.

The parallel dashed line may represent a double bond. When such doublebond is present in the compounds of formula (I), or in any subgroup ofcompounds of formula (I), it may be in a cis or in a transconfiguration.

Preferably, such double bond is in a cis configuration, as depicted informulae (II-1a), (III-1a), (IV-1a), (II-1b), (III-1b), (IV-1b) below.Examples of compounds of the invention have the formulae (II-1a1),(III-1a1), (IV-1a1), (II-1b1), (III-1b1), (IV-1b1), (II-1b2), (III-1b2),(IV-1b2).

wherein a, b, g, h, R³, n, R⁶, R⁷, X and R⁸, where appropriate, have thesame meaning as that defined above or in any of the subgroups ofcompounds of formula (I) specified herein.

A single bond may be present instead of the double bond in themacrocycle of the compounds of formula (I), or in any subgroup ofcompounds of formula (I), as depicted in formulae (II-2a), (III-2a),(IV-2a), (II-2b), (III-2b), (IV-2b), such as for example for compoundsof formulae and (II-2a1), (III-2a1), (IV-2a1), (II-2b1), (III-2b1) or(IV-2b1) below.

wherein a, b, g, h, R³, n, R⁶, R⁷, X and R⁸, where appropriate, have thesame meaning as that defined above or in any of the subgroups ofcompounds of formula (I) specified herein.

An embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV), (II-a), (III-a), (IV-a), (II-b), (III-b),(IV-b), (II-aa), (III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb),(II-bbb), (III-bbb), (IV-bbb), (II-1a), (III-1a), (IV-1a), (II-1b),(III-1b), (IV-1b), (II-1a1), (III-1a1), (IV-1a1), (II-1b1), (III-1b1),(IV-1b1), (II-1b2), (III-1b2), (IV-1b2), (II-2a), (III-2a), (IV-2a),(II-2b), (III-2b), (IV-2b), (II-2a1), (III-2a1), (IV-2a1), (II-2b1),(III-2b1) or (IV-2b1), or of any subgroup thereof, wherein each of a, b,c, d, e, f, g, and h, is, independently, 0, 1, 2, or 3, with the provisothat the macrocycle formed by the bivalent chain R¹, the —C(═O)—NH—moiety and the nitrogen and carbon atoms N1, C6, C7, and C7′ of theindole ring, has from 14 to 16 member atoms.

An embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV), (II-a), (III-a), (IV-a), (II-b), (III-b),(IV-b), (II-aa), (III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb),(II-bbb), (III-bbb), (IV-bbb), (II-1a), (III-1a), (IV-1a), (II-1b),(III-1b), (IV-1b), (II-1a1), (III-1a1), (IV-1a1), (II-1b1), (III-1b1),(IV-1b1), (II-1b2), (III-1b2), (IV-1b2), (II-2a), (III-2a), (IV-2a),(II-2b), (III-2b), (IV-2b), (II-2a1), (III-2a1), (IV-2a1), (II-2b1),(III-2b1) or (IV-2b1), or of any subgroup thereof, wherein R² ishydrogen or C₁₋₄alkyl.

An embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV), (II-a), (III-a), (IV-a), (II-b), (III-b),(IV-b), (II-aa), (III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb),(II-bbb), (III-bbb), (IV-bbb), (II-1a), (III-1a), (IV-1a), (II-1b),(III-1b), (IV-1b), (II-1a1), (III-1a1), (IV-1a1), (II-1b1), (III-1b1),(IV-1b1), (II-1b2), (III-1b2), (IV-1b2), (II-2a), (III-2a), (IV-2a),(II-2b), (III-2b), (IV-2b), (II-2a1), (III-2a1), (IV-2a1), (II-2b1),(III-2b1) or (IV-2b1), or of any subgroup thereof, wherein R³ iscyclopentyl or cyclohexyl.

An embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV), (II-a), (III-a), (IV-a), (II-b), (III-b),(IV-b), (II-aa), (III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb),(II-bbb), (III-bbb), (IV-bbb), (II-1a), (III-1a), (IV-1a), (II-1b),(III-1b), (IV-1b), (II-1a1), (III-1a1), (IV-1a1), (II-1b1), (III-1b1),(IV-1b1), (II-1b2), (III-1b2), (IV-1b2), (II-2a), (III-2a), (IV-2a),(II-2b), (III-2b), (IV-2b), (II-2a1), (III-2a1), (IV-2a1), (II-2b1),(III-2b1) or (IV-2b1), or of any subgroup thereof, wherein R⁷ is phenylor thiazolyl, wherein said phenyl and thiazolyl are each independentlyoptionally substituted with one, two or three substituents eachindependently selected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²;—C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b);—NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹;—SO₂NR^(9a)R^(9b);

phenyl optionally substituted with one, two or three substituents eachindependently selected from halo, trifluoromethyl, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally substituted withone or two substituents each independently selected from oxo,C₁₋₆alkylsulfonyl, and C₁₋₆alkyl; wherein R^(9a) and R^(9b) are eachindependently selected from hydrogen, C₁₋₆alkyl, or arylC₁₋₆alkyl; orR^(9a) and R^(9b), together with the nitrogen to which they areattached, form a saturated, partially unsaturated, or completelyunsaturated 5-8 membered monocycle, wherein said monocycle optionallycontains one additional heteroatom selected from the group consisting ofoxygen, sulfur and nitrogen, and wherein the remaining monocycle membersare carbon atoms; wherein said monocycle is optionally substituted onany carbon atom with one or two substituents each independently selectedfrom halo, C₁₋₆alkyl, hydroxy, or oxo; R¹⁰ is C₁₋₆alkyl orC₃₋₇cycloalkyl; R¹¹ is C₁₋₆alkyl or C₃₋₇cycloalkyl; R¹² is hydrogen orC₁₋₆alkyl; R¹³ is C₁₋₆alkyl; and Het is pyrrolidinyl, piperidinyl,morpholinyl, or piperazinyl.

An embodiment of the present invention concerns compounds of formula(I), (II), (III), (IV), (II-a), (III-a), (IV-a), (II-b), (III-b),(IV-b), (II-aa), (III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb),(II-bbb), (III-bbb), (IV-bbb), (II-1a), (III-1a), (IV-1a), (II-1b),(III-1b), (IV-1b), (II-1a1), (III-1a1), (IV-1a1), (II-1b1), (III-1b1),(IV-1b1), (II-1b2), (III-1b2), (IV-1b2), (II-2a), (III-2a), (IV-2a),(II-2b), (III-2b), (IV-2b), (II-2a1), (III-2a1), (IV-2a1), (II-2b1),(III-2b1) or (IV-2b1), or of any subgroup thereof, wherein R⁸ ishydrogen or phenyl, wherein said phenyl is optionally substituted withone, two, or three substituents each independently selected from halo;cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³;—C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³;—NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b);phenyl optionally substituted with one, two or three substituents eachindependently selected from halo, trifluoromethyl, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally substituted withone or two substituents each independently selected from oxo,C₁₋₆alkylsulfonyl, and C₁₋₆alkyl; wherein R^(9a) and R^(9b) are eachindependently selected from hydrogen, C₁₋₆alkyl, or arylC₁₋₆alkyl; orR^(9a) and R^(9b), together with the nitrogen to which they areattached, form a saturated, partially unsaturated, or completelyunsaturated 5-8 membered monocycle, wherein said monocycle optionallycontains one additional heteroatom selected from the group consisting ofoxygen, sulfur and nitrogen, and wherein the remaining monocycle membersare carbon atoms; wherein said monocycle is optionally substituted onany carbon atom with one or two substituents each independently selectedfrom halo, C₁₋₆alkyl, hydroxy, or oxo; R¹⁰ is C₁₋₆alkyl orC₃₋₇cycloalkyl; R¹¹ is C₁₋₆alkyl or C₃₋₇cycloalkyl; R¹² is hydrogen orC₁₋₆alkyl; R¹³ is C₁₋₆alkyl; and Het is pyrrolidinyl, piperidinyl,morpholinyl, or piperazinyl.

According to an embodiment, the present invention provides compoundshaving one of the structural Formula (I), (II), (III), (IV), (II-a),(III-a), (IV-a), (II-b), (III-b), (IV-b), (II-aa), (III-aa), (IV-aa),(II-bb), (III-bb), (IV-bb), (II-bbb), (III-bbb), (IV-bbb), (II-1a),(III-1a), (IV-1a), (II-1b), (III-1b), (IV-1b), (II-1a1), (III-1a1),(IV-1a1), (II-1b1), (III-1b1), (IV-1b1), (II-1b2), (III-1b2), (IV-1b2),(II-2a), (III-2a), (IV-2a), (II-2b), (III-2b), (IV-2b), (II-2a1),(III-2a1), (IV-2a1), (II-2b1), (III-2b1) or (IV-2b1), wherein

-   R³ is cyclopentyl or cyclohexyl;-   X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;-   R^(5a) and R^(5b) are each independently selected from hydrogen;    C₁₋₂alkyl; haloC₁₋₄alkyl;-   R⁶ is hydrogen, C₁₋₆alkyl, or fluoro;-   n is 1, or 2;-   R⁷ is phenyl or thiazolyl, wherein each phenyl is optionally    substituted with one, two, or three substituents, wherein each    thiazolyl is optionally substituted with one or two substituents;    wherein the substituents on both phenyl and thiazolyl are each    independently selected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²;    —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b);    —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹;    —SO₂NR^(9a)R^(9b); phenyl optionally substituted with one, two or    three substituents each independently selected from halo,    trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and    —C(═O)NR^(9a)R^(9b); and Het optionally substituted with one or two    substituents each independently selected from oxo,    C₁₋₆alkyl-sulfonyl, and C₁₋₆alkyl;-   R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one, two, or three substituents each independently    selected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²;    —C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³;    —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b);    phenyl optionally substituted with one, two or three substituents    each independently selected from halo, trifluoromethyl, cyano,    C₁₋₆alkyl, C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally    substituted with one or two substituents each independently selected    from oxo, C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   R^(9a) and R^(9b) are each independently selected from hydrogen,    C₁₋₆alkyl, or arylC₁₋₆alkyl; or R^(9a) and R^(9b), together with the    nitrogen to which they are attached, form a saturated, partially    unsaturated, or completely unsaturated 5-8 membered monocycle,    wherein said monocycle optionally contains one additional heteroatom    selected from the group consisting of oxygen, sulfur and nitrogen,    and wherein the remaining monocycle members are carbon atoms;    wherein said monocycle is optionally substituted on any carbon atom    with one or two substituents each independently selected from halo,    C₁₋₆alkyl, hydroxy, or oxo;-   R¹⁰ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R¹¹ is C₁₋₆alkyl or C₃₋₇cycloalkyl;-   R¹² is hydrogen or C₁₋₆alkyl;-   R¹³ is C₁₋₆alkyl;-   Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

According to another embodiment, the present invention providescompounds having one of the structural Formula (I), (II), (III), (IV),(II-a), (III-a), (IV-a), (II-b), (III-b), (IV-b), (II-aa), (III-aa),(IV-aa), (II-bb), (III-bb), (IV-bb), (II-bbb), (III-bbb), (IV-bbb),(II-1a), (III-1a), (IV-1a), (II-1b), (III-1b), (IV-1b), (II-1a1),(III-1a1), (IV-1a1), (II-1b1), (III-1b1), (IV-1b1), (II-1b2), (III-1b2),(IV-1b2), (II-2a), (III-2a), (IV-2a), (II-2b), (III-2b), (IV-2b),(II-2a1), (III-2a1), (IV-2a1), (II-2b1), (III-2b1) or (IV-2b1), wherein

-   R³ is cyclopentyl or cyclohexyl;-   X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—; R^(5a) and R^(5b)    are each independently selected from hydrogen; methyl, ethyl;    trifluoromethyl;-   R⁶ is hydrogen, C₁₋₄alkyl, or fluoro;-   n is 1, or 2;-   R⁷ is phenyl or thiazolyl, wherein said phenyl and thiazolyl are    each independently optionally substituted with one or two    substituents each independently selected from halo; cyano; nitro;    C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b);    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b);    —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b); phenyl optionally substituted    with one or two substituents each independently selected from halo,    trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and    —C(═O)NR^(9a)R^(9b); and Het optionally substituted with one or two    substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one or two substituents each independently selected    from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³;    —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; phenyl    optionally substituted with one or two substituents each    independently selected from halo, trifluoromethyl, cyano, C₁₋₆alkyl,    C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally substituted    with one or two substituents each independently selected from oxo,    C₁₋₆alkylsulfonyl, and C₁₋₆alkyl;-   R^(9a) and R^(9b) are each independently selected from hydrogen or    C₁₋₆alkyl;-   R¹² is hydrogen or C₁₋₆alkyl;-   R¹³ is C₁₋₆alkyl;-   Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

According to another embodiment, the present invention providescompounds having one of the structural Formula (I), (II), (III), (IV),(II-a), (III-a), (IV-a), (II-b), (III-b), (IV-b), (II-aa), (III-aa),(IV-aa), (II-bb), (III-bb), (IV-bb), (II-bbb), (III-bbb), (IV-bbb),(II-1a), (III-1a), (IV-1a), (II-1b), (III-1b), (IV-1b), (II-1a1),(III-1a1), (IV-1a1), (II-1b1), (III-1b1), (IV-1b1), (II-1b2), (III-1b2),(IV-1b2), (II-2a), (III-2a), (IV-2a), (II-2b), (III-2b), (IV-2b),(II-2a1), (III-2a1), (IV-2a1), (II-2b1), (III-2b1) or (IV-2b1), wherein

-   R³ is cyclohexyl;-   X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;-   R^(5a) and R^(5b) are each independently selected from hydrogen;    methyl, ethyl; or trifluoromethyl;-   R⁶ is hydrogen or fluoro;-   n is 1;-   R⁷ is phenyl or thiazolyl, wherein said phenyl and thiazolyl are    each independently optionally substituted with one or two    substituents each independently selected from halo; nitro;    C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b);    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b);    phenyl optionally substituted with one or two substituents each    independently selected from halo, trifluoromethyl, C₁₋₆alkyl, and    C₁₋₆alkoxy; and Het optionally substituted with C₁₋₆alkylsulfonyl;-   R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one or two substituents each independently selected    from halo; nitro; —OR¹²; —C(═O)OR¹²; —C(═O)NR^(9a)R^(9b);    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; phenyl optionally substituted with    halo; and Het optionally substituted with one or two substituents    each independently selected from oxo or C₁₋₆alkylsulfonyl;-   R^(9a) and R^(9b) are each independently selected from hydrogen or    C₁₋₆alkyl;-   R¹² is hydrogen or C₁₋₆alkyl;-   R¹³ is C₁₋₆alkyl;-   Het is pyrrolidinyl, morpholinyl, or piperazinyl.

According to an embodiment, the present invention provides compoundshaving one of the structural Formula (I), (II), (III), (IV), (II-a),(III-a), (IV-a), (II-b), (III-b), (IV-b), (II-aa), (III-aa), (IV-aa),(II-bb), (III-bb), (IV-bb), (II-bbb), (III-bbb), (IV-bbb), (II-1a),(III-1a), (IV-1a), (II-1b), (III-1b), (IV-1b), (II-1a1), (III-1a1),(IV-1a1), (II-1b1), (III-1b1), (IV-1b1), (II-1b2), (III-1b2), (IV-1b2),(II-2a), (III-2a), (IV-2a), (II-2b), (III-2b), (IV-2b), (II-2a1),(III-2a1), (IV-2a1), (II-2b1), (III-2b1) or (IV-2b1), wherein

-   X is selected from —CR^(5a)R^(5b)— or —NR^(5a)—;-   R^(5a) and R^(5b) are each independently selected from hydrogen;    methyl, or trifluoromethyl;-   n is 1;-   R⁶ is selected from hydrogen or fluoro;-   R⁷ is phenyl or thiazolyl, wherein said phenyl and thiazolyl are    each independently optionally substituted with one or two,    preferably two substituents each independently selected from halo;    nitro; C₁₋₆alkyl; —OR¹²; phenyl optionally substituted with one, two    or three halo substituents;-   R⁸ is hydrogen, or phenyl, wherein said phenyl is optionally    substituted with one or two, preferably two substituents each    independently selected from halo; nitro; C₁₋₃alkyl; —OR¹²;    —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; phenyl optionally substituted with    halo; and Het optionally substituted with one or two substituents    each independently selected from oxo, and C₁₋₃alkylsulfonyl;-   R^(9a) and R^(9b) are each independently selected from hydrogen or    C₁₋₃alkyl;-   R¹² is hydrogen or C₁₋₃alkyl;-   R¹³ is C₁₋₃alkyl;-   Het is pyrrolidinyl, morpholinyl, or piperazinyl.

It is to be understood that the above defined subgroups of compounds offormulae (I), (II), (III), (IV), (II-a), (III-a), (IV-a), (II-b),(III-b), (IV-b), (II-aa), (III-aa), (IV-aa), (II-bb), (III-bb), (IV-bb),(II-bbb), (III-bbb), (IV-bbb), (II-1a), (III-1a), (IV-1a), (II-1b),(III-1b), (IV-1b), (II-1a1), (III-1a1), (IV-1a1), (II-1b1), (III-1b1),(IV-1b1), (II-1b2), (III-1b2), (IV-1b2), (II-2a), (III-2a), (IV-2a),(II-2b), (III-2b), (IV-2b), (II-2a1), (III-2a1), (IV-2a1), (II-2b1),(III-2b1) or (IV-2b1) as well as any other subgroup defined herein, aremeant to also comprise any N-oxides, salts, quaternary amines, metalcomplexes and stereochemically isomeric forms of such compounds.

Yet another embodiment relates to the compounds of formula (V) whereinone or more of the following restrictions apply:

-   (a) R¹ is a bivalent chain of formula

wherein the points of attachment are as defined above;

-   (b) R³ is cyclohexyl;-   (c) R⁶ is hydrogen;-   (d) R^(6a) is halo or hydrogen.

One embodiment relates to the compounds of formula (I) or any subgroupthereof wherein R¹ is a bivalent chain of formula

and wherein one or more of the following restrictions apply:

-   -   (a) X is NH or CH₂;    -   (b) g is 1;    -   (c) h is 2;    -   (d) R² is C₁₋₄alkyl, preferably methyl;    -   (e) R³ is cyclohexyl;    -   (f) R⁴ is a group selected from

-   -   preferably a group selected from

Another embodiment relates to the compounds of formula (I) or anysubgroup thereof wherein R⁴ is phenyl, p-methoxy-phenyl orp-halo-phenyl.

Preparation of the Compounds of Formula (I)

The compounds of formula (I) and the salts and stereoisomers thereof,wherein R¹ is the bivalent chain

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents isattached to the remainder of the molecule via the nitrogen atom of theamide group, and the carbon atom of the acetamide moiety is attached tothe remainder of the molecule via the nitrogen atom of the indole ringof the compound of formula (I);

-   each of a, and b is, independently, 0, 1, 2, or 3, with the proviso    that the macrocycle formed by the bivalent chain R¹, the —C(═O)—NH—    moiety to which R¹ is attached and the nitrogen and carbon atoms N1,    C6, C7, and C7′ of the indole ring, has from 14 to 17 member atoms;    and    the parallel dashed line (represented by    ) represents an optional double bond;    may be prepared according to Scheme I, as depicted below, wherein i    is an integer equal to a+1, and b, R³ and R⁴ have the same meaning    as that defined above.

The compound of formula (B), i.e. a 3-substituted indole, may beobtained by condensation of a C₄₋₇cycloalkanone with the indole offormula (A) followed by a reduction. C₄₋₇cycloalkanone is the precursorof the R³ substituent: C₄₋₇cycloalkyl, as defined for the compounds offormula (I) or any subgroup thereof.

Condensation of the C₄₋₇cycloalkanone with the indole of formula (A) maybe carried out in a suitable solvent such as methanol or ethanol, in thepresence of a base such as sodium methanolate or potassiumtert-butoxide. The C₄₋₇cycloalkanone, once introduced into compound offormula (B), is attached to the indole as a C₄₋₇cycloalkenyl. BothC₄₋₇cycloalkanone and the compound of formula (A) are commerciallyavailable. Reduction of the double bond in the C₄₋₇cycloalkenyl moietymay be achieved using an appropriate catalyst (Pd(OH)₂/C) in a suitablesolvent such as methanol, ethanol, THF, or a mixture thereof, and byapplying a pressure between atmospheric pressure and 80 psi.

Esterification of the acid in compound of formula (B) by standardprocedures generates compound of formula (C). Standard procedures foresterification of an acid are known by the skilled in the art andinclude amongst other, adding thionyl chloride in a solution of the acidin methanol, or adding methanol in the presence of an acid such assulfuric acid.

Compound of formula (D) may be obtained by brominating the indole offormula (C) with a bromination agent such as bromine or pyridinetribromide, in an appropriate solvent such as THF, chloroform,dichloromethane or carbon tetrachloride.

Compound of formula (I-a1) may be obtained by a palladium couplingreaction between the 2-bromoindole of formula (D) and a boronic acidderivative (including ester derivatives) carrying the R⁴ group, in thepresence of a palladium derivative at a temperature between 20° C. and100° C., in an appropriate solvent such as ethanol, water, acetonitrile,toluene, or a mixture thereof.

Compound of formula (I-a2) may be obtained by alkylation at position 1of the indole of formula (I-a1) using a haloacetate derivative in thepresence of a base such as sodium hydride, potassium carbonate, cesiumcarbonate, and the like, in the presence of a suitable solvent such asDMF, THF, acetonitrile and the like.

Compound of formula (I-a3) may be obtained by carrying out a hydrolysison compound of formula (I-a2) in acid media or via saponification usinga hydroxide, for instance LiOH or NaOH, in polar solvents such as water,an alcohol such as methanol or ethanol, THF, or a mixture thereof.

Compound of formula (I-a5) may be prepared by an amide forming reactionstarting from intermediate (I-a3) which is reacted with an alkenylamine(I-a4) as shown in Scheme I.

The formation of amide bonds can be carried out using standardprocedures such as those used for coupling amino acids in peptidesynthesis. The latter involves the dehydrative coupling of a carboxylgroup of one reactant with an amino group of the other reactant to forma linking amide bond. The amide bond formation may be performed byreacting the starting materials in the presence of a coupling agent orby converting the carboxyl functionality into an active form such as anactive ester, mixed anhydride or a carboxyl acid chloride or bromide.General descriptions of such coupling reactions and the reagents usedtherein can be found in general textbooks on peptide chemistry, forexample, M. Bodanszky, “Peptide Chemistry”, 2nd rev. ed.,Springer-Verlag, Berlin, Germany, (1993).

Examples of coupling reactions with amide bond formation include theazide method, mixed carbonic-carboxylic acid anhydride (isobutylchloroformate) method, the carbodiimide (dicyclohexylcarbodiimide,diisopropylcarbodiimide, or water-soluble carbodiimide such asN-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide) method, the activeester method (e.g. p-nitrophenyl, p-chlorophenyl, trichlorophenyl,pentachloro-phenyl, pentafluorophenyl, N-hydroxysuccinic imido and thelike esters), the Woodward reagent K-method, the 1,1-carbonyldiimidazole(CDI or N,N′-carbonyl-diimidazole) method, the phosphorus reagents oroxidation-reduction methods. Some of these methods can be enhanced byadding suitable catalysts, e.g. in the carbodiimide method by adding1-hydroxybenzotriazole, or 4-DMAP. Further coupling agents are(benzotriazol-1-yloxy)-tris-(dimethylamino) phosphoniumhexafluorophosphate, either by itself or in the presence of1-hydroxy-benzotriazole or 4-DMAP; or2-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetra-methyluroniumtetrafluoroborate, orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate. These coupling reactions can be performed in eithersolution (liquid phase) or solid phase.

A preferred amide bond formation is performed employingN-ethyloxycarbonyl-2-ethyl-oxy-1,2-dihydroquinoline (EEDQ) orN-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline (IIDQ). Unlikethe classical anhydride procedure, EEDQ and IIDQ do not require base norlow reaction temperatures. Typically, the procedure involves reactingequimolar amounts of the carboxyl and amine components in an organicsolvent (a wide variety of solvents can be used). Then EEDQ or IIDQ isadded in excess and the mixture is allowed to stir at room temperature.

The coupling reactions preferably are conducted in an inert solvent,such as halogenated hydrocarbons, e.g. dichloromethane, chloroform,dipolar aprotic solvents such as acetonitrile, dimethylformamide,dimethylacetamide, DMSO, HMPT, ethers such as tetrahydrofuran (THF).

In many instances the coupling reactions are done in the presence of asuitable base such as a tertiary amine, e.g. triethylamine,diisopropylethylamine (DIPEA), N-methyl-morpholine, N-methylpyrrolidine,4-DMAP or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reactiontemperature may range between 0° C. and 50° C. and the reaction time mayrange between 15 min and 24 h.

Formation of the macrocycle, i.e. compound of formula (I-a) can becarried out via an olefin metathesis reaction in the presence of asuitable metal catalyst such as e.g. the Ru-based catalyst reported byMiller, S. J., Blackwell, H. E., Grubbs, R. H. J. Am. Chem. Soc. 118,(1996), 9606-9614; Kingsbury, J. S., Harrity, J. P. A., Bonitatebus, P.J., Hoveyda, A. H., J. Am. Chem. Soc. 121, (1999), 791-799; and Huang etal., J. Am. Chem. Soc. 121, (1999), 2674-2678; for example aHoveyda-Grubbs catalyst.

Air-stable ruthenium catalysts such asbis(tricyclohexylphosphine)-3-phenyl-1H-inden-1-ylidene rutheniumchloride (Neolyst M1®) orbis(tricyclohexylphosphine)-[(phenylthio)methylene]ruthenium (IV)dichloride can be used. Other catalysts that can be used are Grubbsfirst and second generation catalysts, i.e.benzylidene-bis(tricyclo-hexylphosphine)dichlororuthenium and(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium,respectively. Of particular interest are the Hoveyda-Grubbs first andsecond generation catalysts, which aredichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)-ruthenium(II)and1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro-(o-isopropoxyphenylmethylene)rutheniumrespectively. Also, other catalysts containing other transition metalssuch as Mo can be used for this reaction.

The metathesis reactions may be conducted in a suitable solvent such asfor example ethers, e.g. THF, dioxane; halogenated hydrocarbons, e.g.dichloromethane, CHCl₃, 1,2-dichloroethane and the like, hydrocarbons,e.g. toluene. These reactions are conducted at increased temperaturesunder nitrogen atmosphere.

Alternatively, compound of formula (I-a) may be obtained by coupling thediacid (I-a3) with a diamine using diluted conditions.

In an embodiment, compounds of formula (III-1a) can be preparedaccording to Scheme II, as depicted below, wherein i is an integer equalto a+1, and b, n, R³, R⁶ and R⁸ have the same meaning as that definedabove.

In Scheme II, compound of formula (III-a1) is reacted with compound offormula (III-a2) via a Mitsunobu reaction (Mitsunobu, 1981, Synthesis,January, 1-28; Rano et al., Tetrahedron Lett., 1995, 36, 22, 3779-3792;Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter etal., Tetrahedron Lett., 1994, 35, 27, 4705-4706) to obtain compound offormula (III-a3). This reaction comprises treatment of intermediate(III-a1) with intermediate (III-a2), in the presence oftriphenylphosphine or tris(tert-butyl)phosphine and an activating agentsuch as a dialkyl azodicarboxylate, e.g. diethyl azodicarboxylate(DEAD), diisopropyl azodicarboxylate (DIAD) or the like. Suitablesolvents for this reaction are dimethylformamide (DMF) ortetrahydrofuran (THF), and the temperature of the reaction may varybetween −20° C. and +50° C.

Alternatively, the compound of formula (III-a3) can be generated byreacting the compound of formula (III-a1) with the halo-derivative offormula (III-a2), i.e. compound of formula (E) as depicted below whereinZ is halo, via an alkylation with a base such as potassium carbonate,cesium carbonate, sodium hydride, or potassium tert-butoxide, in thepresence of a suitable solvent such as DMF, THF, or acetonitrile.

Compound of formula (III-a4) may be obtained by carrying out ahydrolysis on compound of formula (III-a3) in acid media or viasaponification using a hydroxide, for instance LiOH or NaOH, in polarsolvents such as water, an alcohol such as methanol or ethanol, THF, ora mixture thereof.

Compound of formula (III-a5) may be prepared by an amide formingreaction starting from intermediate (III-a4) which is reacted with analkenylamine (I-a4) as shown in Scheme II.

The formation of amide bonds can be carried out using standardprocedures such as those used for coupling amino acids in peptidesynthesis described above for scheme I.

Formation of the macrocycle, i.e. compound of formula (III-1a), can becarried out via an olefin metathesis reaction in the presence of asuitable metal catalyst such as e.g. the Ru-based catalyst as reportedabove for the formation of the macrocycle of formula (I-a).

Alternatively, compound of formula (III-1a) may be obtained by couplingthe diacid (III-a4) with a diamine using diluted conditions.

Compound of formula (III-a1) may be generated according to the proceduredepicted in Scheme III, wherein R³ and R⁶ have the same meaning as thatdefined above and PG is a suitable protecting group.

Compound of formula (III-a7) may be obtained by a palladium couplingreaction between the 2-bromoindole of formula (D) and a boronic acidderivative (including ester derivatives) carrying a R⁶-substitutedphenyl, in the presence of a palladium derivative at a temperaturebetween 20° C. and 100° C., in an appropriate solvent such as ethanol,water, acetonitrile, toluene, or a mixture thereof. The R⁶-substitutedphenyl is optionally protected, as shown in Scheme III, wherein PG is ahydroxyl-protecting group. Hydroxyl groups may be protected as benzyl orsubstituted benzyl ethers, e.g. 4-methoxybenzyl ether, benzoyl orsubstituted benzoyl esters, e.g. 4-nitrobenzoyl ester, or withtrialkylsilyl groups (e.g. trimethylsilyl or tert-butyldimethylsilyl).Further appropriate protecting groups that can be used are listed forexample in Greene, “Protective Groups in Organic Chemistry”, John Wiley& Sons, New York (1999) and “The Peptides: Analysis, Synthesis,Biology”, Vol. 3, Academic Press, New York (1987).

Compound of formula (III-a8) may be obtained by alkylation at position 1of the indole of formula (III-a7) using a haloacetate derivative in thepresence of a base such as sodium hydride, potassium carbonate, cesiumcarbonate, and the like, in the presence of a suitable solvent such asDMF, THF, acetonitrile and the like.

Compound of formula (III-a1) may be obtained by unmasking ordeprotecting the hydroxyl in compound of formula (III-a8), by usinghydrogenation in the presence of a catalyst such as Pd/C in a suitablesolvent such as methanol, ethanol, THF, or a mixture thereof, and thelike, and by applying a pressure between atmospheric pressure and 80psi. Other unmasking or deprotecting methods known in the art may beused.

In one embodiment of the present invention, in the compound of formula(III-a2)

n is 1;R⁸ is phenyl substituted with one Het that is optionally substitutedwith one or two substituents each independently selected from oxo,C₁₋₆alkylsulfonyl, and C₁₋₆alkyl; and said phenyl is as well optionallysubstituted with one or two R¹⁵ substituents;R¹⁵ is halo; cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³;—C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³;—NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b); orphenyl optionally substituted with one, two or three substituents eachindependently selected from halo, trifluoromethyl, C₁₋₆alkyl, andC₁₋₆alkoxy;Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl,and R^(9a), R^(9b), R¹⁰, R¹¹, R¹², and R¹³, have the same meaning asthat defined above.

Examples of compound of formula (III-a2), such as compound of formula(J), may be prepared according to the procedure depicted in Scheme IVbelow, wherein R¹⁵ has the same meaning as that defined above, Y is ahalo, and Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl,wherein Het is optionally substituted with oxo, C₁₋₆alkylsulfonyl orC₁₋₆alkyl.

Introduction of an optionally substituted Het group into the compound offormula (G) to afford the benzoic acid derivative (H) may be performedby an aromatic nucleophilic substitution of the 2-halobenzoic acidderivative (G) with a nucleophilic amine, optionally in the presence ofa base, in an appropriate solvent such as DMF, THF, or acetonitrile.Obviously, the nucleophilic amine refers to the optionally substitutedHet group.

Compound of formula (G) is commercially available. Y represents a halosubstituent in the compound of formula (G).

The Het compound, which may be a pyrrolidinyl, piperidinyl, morpholinyl,or piperazinyl, and is optionally substituted with oxo,C₁₋₆alkylsulfonyl, or C₁₋₆alkyl, is also commercially available.

The acid of compound of formula (H) is then esterified in order toproduce the compound of formula (K). Esterification may be performedaccording to several methods known by the skilled in the art, includingamongst other, the use of methyl iodide in the presence of a base in anappropriate solvent such as DMF, THF or acetonitrile.

Compound of formula (J), which is a particular embodiment of compound offormula (III-a2), may be then obtained by reduction of the ester offormula (K) using a hydride such as LiAlH₄ in an appropriate solventsuch as THF.

Alternatively, a compound (G) may be esterified first to produce forexample a methyl ester derivative, prior to the introduction of the Hetgroup. Furthermore, before transforming (K) to (J), when R¹⁵ is nitro, acatalytic hydrogenation may be performed to get a compound of formula(K) where R¹⁵ is amino. This amino group may be further transformed intoa group of formula NR^(9a)R^(9b).

Compounds of formula (I) wherein the macrocycle contains no double bond,i.e. such as for example compounds of formula (II-2a), (III-2a),(IV-2a), can be prepared from the compounds of formula (I-a) by areduction of the double bond. This reduction may be conducted bycatalytic hydrogenation with hydrogen in the presence of a noble metalcatalyst such as, for example, Pt, Pd, Rh, Ru or Raney nickel. Ofinterest is Rh on alumina. The hydrogenation reaction preferably isconducted in a solvent such as, e.g. an alcohol such as methanol,ethanol, or an ether such as THF, or mixtures thereof. Water can also beadded to these solvents or solvent mixtures.

Alternative methods for the preparation of the compounds of the presentinvention encompass the procedure as depicted in Scheme V below, whereini is an integer equal to a+1, and R³, b, and R⁴ have the same meaning asthat defined above.

The compound of formula (I-a6) may be obtained from intermediate (D) bythe alkylation procedure as described for compound of formula (I-a2)above.

Compound of formula (I-a6) is then submitted to a hydrolysis in acidmedia or to a saponification as described for compound of formula(I-a2), in order to generate compound of formula (I-a7).

Compound of formula (I-a8) may be prepared by an amide forming reactionby reacting intermediate (I-a7) with an alkenylamine (I-a4), asdescribed for compound of formula (I-a5).

Ring closure by an olefin metathesis reaction is then carried out inorder to produce compound of formula (I-a9), which is then reacted witha boronic acid derivative (including ester derivatives) carrying the R⁴group, following the procedures described for compound of formula (I-al)above. Compound of formula (I-a) is then obtained.

In an embodiment, compounds of formula (III-1a) can be preparedaccording to Scheme VI, as depicted below, wherein i is an integer equalto a+1, and R³, b, n, R⁶, PG and R⁸ have the same meaning as thatdefined above.

Compound of formula (I-a9) is reacted with a boronic acid derivative(including ester derivatives) carrying a R⁶-substituted phenyl,following the procedures described for compound of formula (III-a7)above. Compound of formula (III-a9) is then obtained.

Unmasking or deprotection of the hydroxyl in compound of formula(III-a9) leads to compound of formula (III-a10), which is then coupledto intermediate (III-a2) or (E) through a Mitsunobu or an alkylationreaction, respectively, as described above. Compound of formula (III-1a)is then obtained.

The compounds of formula (I) and the salts and stereoisomers thereof,wherein R¹ is the bivalent chain

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents isattached to the remainder of the molecule via the nitrogen atom of theamide group, and the carbon atom of the acetamide moiety is attached tothe remainder of the molecule via the nitrogen atom of the indole ringof the compound of formula (I);each of h, and g is, independently, 0, 1, 2, or 3, with the proviso thatthe macrocycle formed by the bivalent chain R¹, the —C(═O)—NH— moiety towhich R¹ is attached and the nitrogen and carbon atoms N1, C6, C7, andC7′ of the indole ring, has from 14 to 17 member atoms;may be prepared according to Scheme VII, as depicted below, wherein R³,R⁴, and X have the same meaning as that defined above.

Sulfonamide compounds (I-b) may be obtained as described in scheme VII.

A compound of formula (I-a 10) may be obtained from an intermediate(I-a2) by regioselective cleavage of the acetic acid methylester moiety,for example by saponification at low temperature, such as 0° C.

A compound of formula (I-a12) may be prepared by an amide formingreaction by reacting intermediate (I-a 10) with an alkenylamine (I-a11),as described above for compound of formula (I-a5).

A compound of formula (I-a12) is then submitted to a hydrolysis in acidmedia or to a saponification as described for compound of formula(I-a3), in order to generate a compound of formula (I-a13).

A compound of formula (I-a15) may be obtained by coupling anintermediate (I-a13) with a sulfonamide (I-a14) in the presence ofcoupling agents, such as EDCI, in the presence of DMAP.

Ring closure by an olefin metathesis reaction is then carried out inorder to produce a compound of formula (I-b).

Compounds of formula (I) may be converted into each other followingart-known functional group transformation reactions. For example, aminogroups may be N-alkylated, nitro groups reduced to amino groups, a haloatom may be exchanged for another halo.

In the previous scheme (I), an intermediate of formula (L) may be usedas an alternative instead of an intermediate of formula (D). Thiscompound (L) may be synthesized as described in US2007270405 A1. Whenusing said alternative for an intermediate of formula (D), the methylester in the intermediates (I-a1), (I-a2), (III-al), (III-a3), (III-a7),(III-a8), (I-a6), (I-a10) and (I-a12) as described in schemes (I), (II),(III), (V) and (VII), is replaced by the tertbutyl group. For thesubsequent hydrolysis of this tertbutyl ester group, acidic conditionsmay be used, such as TFA in DCM, or HCl in isopropanol or anothersuitable organic solvent.

In schemes (VIII) and (IX), the group A is defined as the chaincomprised between the carbonyl group and the sulfonyl group of thebivalent chains R¹ as shown below.

Such acylsulfonamide forming bivalent chains are generally depicted asfollows:

A schematic overview for the synthesis of the compounds of formula (I)bearing the acylsulfonamide chains described above is given in scheme(VIII). The method starts from a compound of formula (I-a16), where Raand Rb may be a methyl group or a tertbutyl group, with the provisiothat compounds (I-a16) have only one tertbutyl group (if Ra is tertbutylthen Rb is methyl, and vice-versa) and wherein R³ and R⁴ have the samemeaning as that defined above or in any of the subgroups of compounds offormula (I) specified herein.

Compounds of formula I-a17 may be prepared by the regioselectivehydrolysis of the ester bearing the Ra group, under basic conditions,using a hydroxide such as LiOH or NaOH, in polar solvents such as water,an alcohol such as methanol or ethanol, tetrahydrofurane (THF), or amixture thereof, and at low temperature, for example 0° C. This methodmay be used when Ra is a methyl group. The regioselective hydrolysis ofthe ester bearing the Ra group may also be performed under acidicconditions when Ra is a tertbutyl group, using for example HCl in anappropriate organic solvent such as isopropanol, or TFA in DCM forexample.

A monoprotected bifunctional derived reagent of formula PG-A-H wherein Ais as defined above, may then be coupled to the carboxylic acid ofcompounds I-a17 to form an amide bond, leading to compounds I-a18. “PG”,as used herein, is a suitable amine protecting group, chosen from theones known in the art. Preferably PG is a tert-butyloxy carbonyl (Boc)protecting group or a 2-nitrobenzenesulfonyl (nosyl) group.

The formation of amide bonds can be carried out using standardprocedures such as those used for coupling amino acids in peptidesynthesis. The latter involves the dehydrative coupling of a carboxylgroup of one reactant with an amino group of the other reactant to forma linking amide bond. The amide bond formation may be performed byreacting the starting materials in the presence of a coupling agent orby converting the carboxyl functionality into an active form such as anactive ester, mixed anhydride or a carboxyl acid chloride or bromide.General descriptions of such coupling reactions and the reagents usedtherein can be found in general textbooks on peptide chemistry, forexample, M. Bodanszky, “Peptide Chemistry”, 2nd rev. ed.,Springer-Verlag, Berlin, Germany, (1993).

Examples of coupling reactions with amide bond formation include theazide method, mixed carbonic-carboxylic acid anhydride (isobutylchloroformate) method, the carbodiimide (dicyclohexylcarbodiimide (DCC),diisopropylcarbodiimide (DIC), or water-soluble carbodiimide such asN-ethyl-N′-[3-(dimethylamino)propyl]carbodiimide (EDC)) method, theactive ester method (e.g. p-nitrophenyl, p-chlorophenyl,trichlorophenyl, pentachlorophenyl, pentafluorophenyl, N-hydroxysuccinicimido and the like esters), the Woodward reagent K-method, the1,1-carbonyldiimidazole (CDI or N,N′-carbonyldiimidazole) method, thephosphorus reagents or oxidation-reduction methods. Some of thesemethods can be enhanced by adding suitable catalysts, e.g. in thecarbodiimide method by adding 1-hydroxybenzotriazole, or4-dimethylamino-pyridine (4-DMAP). Further coupling agents are(benzotriazol-1-yloxy)-tris-(dimethylamino) phosphoniumhexafluorophosphate, either by itself or in the presence of1-hydroxy-benzotriazole or 4-DMAP; or2-(1H-benzotriazol-1-yl)-N,N,N′,R′-tetra-methyluroniumtetrafluoroborate, orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate. These coupling reactions can be performed in eithersolution (liquid phase) or solid phase.

The coupling reactions preferably are conducted in an inert solvent,such as halogenated hydrocarbons, e.g. dichloromethane (DCM),chloroform, dipolar aprotic solvents such as acetonitrile,dimethylformamide (DMF), dimethylacetamide, DMSO, HMPT, ethers such astetrahydrofuran (THF).

In many instances the coupling reactions are done in the presence of asuitable base such as a tertiary amine, e.g. triethylamine,diisopropylethylamine (DIPEA), N-methyl-morpholine, N-methylpyrrolidine,4-DMAP or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reactiontemperature may range between 0° C. and 50° C. and the reaction time mayrange between 15 min and 24 h.

Removal of the protecting group following methods known in the art maylead to compounds I-a19. These methods include the reaction of compoundsI-a18 with trifluoro acetic acid (TFA) in a suitable solvent such asDCM, when PG is a Boc-protecting group, or the reaction of compoundsI-a18 with a thiol like mercapto acetic acid or thiophenol, in solutionor in solid phase, in the presence of a base, such as cesium carbonateor LiOH, in a suitable solvent, such as DMF, THF when PG is nosyl.

Compounds I-a19 are then reacted with sulfamide, in a suitable solvent,for example dioxane, under heating conditions, eg 100° C. This reactionmay take place under microwave irradiation and lead to compounds I-a20.Another method to introduce the sulfamide moiety may consist of thereaction of compound I-a18 with aminosulfonyl-chloride, in the presenceof a suitable base, such as triethylamine, DIPEA, or pyridine, in asuitable solvent, such as a chlorinated solvent like DCM, or DMF, THF.

The ester function of compounds I-a20 may then be hydrolyzed, usingconditions known in the art, and including the saponification in basicmedia as described above, leading to compounds I-a21. Heating may berequired to complete this reaction. Acidic conditions, such as TFA inDCM or HCl in isopropanol, may also be used when Rb is a tertbutylgroup.

Compounds (I) bearing the acylsulfonamide chains may be obtained bymacrocyclisation by forming the intramolecular acylsulfamide bond, inthe presence of coupling agents, such as CDI which converts thecarboxylic acid group to a reactive species acylimidazole, underheating. This acylimidazole may then be purified before adding asuitable base such as DBU, in order to perform the ring closure, whichmay take place under heating conditions. Solvents used for thesereactions may include acetonitrile or THF. Other coupling agents, suchas those known in the art, may also be used to achieve the ring closure.

An alternative method leading to compounds I-a19 as illustrated inscheme (IX), may be the formation of an amide bond between compoundsI-a17 and a symmetrical bivalent chain, used in excess compared tocompounds I-a17. This amide bond may be synthesized as described above,in particular using a coupling agent such as[dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate (HATU), in the presence of a base such as DIPEA andin a suitable solvent like DCM, DMF, or more preferably THF. CompoundsI-a19 may then be reacted as described above in scheme (VIII) in orderto prepare compounds (I) bearing the acylsulfonamide chains.

Compounds of formula (I), wherein R¹ are the bivalent chains

wherein R^(5a), R^(5b), a, b, c, d, e, f and R² have the same meaning asdefined earlier, may be synthesized following scheme (X), wherein Bstands for any one of the following chains

Compounds of formula (I-a22), obtained analogous to the route describedin scheme (VIII) by replacing group A by group B, may be cyclized byforming an intramolecular amide bond using standard procedures such asthose used for coupling amino acids in peptide synthesis described abovefor scheme (I). Preferably the macrocyclisation is performed with acoupling reagent such as HATU, in the presence of a base such as DIPEA,in a suitable organic solvent such as DMF, THF, CH3CN or DCM, under highdilution conditions. Those conditions may be obtained by adding dropwisea solution of compound (I-a22) to a solution of the above mentionedreagents.

Compounds of formula (I) wherein R¹ are the bivalent chains

wherein R^(5a), R^(5b), a, b, g and h have the same meaning as definedearlier, may be reduced following methods known in the art, such ascatalytic hydrogenation, using for example Pd/C as a catalyst, in asuitable solvent such as methanol, ethanol, THF, acetic acid or amixture thereof, to yield compounds of formula I-2a or I-2b, where thealkene of the bivalent chain R¹ is reduced to the corresponding alkane.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarbo-peroxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzene-carboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert-butyl hydroperoxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., counter-current distribution,liquid chromatography and the like.

The compounds of formula (I) may be obtained as racemic mixtures ofenantiomers which can be separated from one another following art-knownresolution procedures. The racemic compounds of formula (I), which aresufficiently basic or acidic may be converted into the correspondingdiastereomeric salt forms by reaction with a suitable chiral acid,respectively chiral base. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkali oracid. An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography, in particularliquid chromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound may be synthesized by stereospecific methods ofpreparation. These methods may advantageously employ enantiomericallypure starting materials.

In a further aspect, the present invention concerns a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) as specified herein, or a compound of any of thesubgroups of compounds of formula (I) as specified herein, and apharmaceutically acceptable carrier. A therapeutically effective amountin this context is an amount sufficient to prophylactically act against,to stabilize or to reduce viral infection, and in particular HCV viralinfection, in infected subjects or subjects being at risk of beinginfected. In still a further aspect, this invention relates to a processof preparing a pharmaceutical composition as specified herein, whichcomprises intimately mixing a pharmaceutically acceptable carrier with atherapeutically effective amount of a compound of formula (I), asspecified herein, or of a compound of any of the subgroups of compoundsof formula (I) as specified herein.

Therefore, the compounds of the present invention or any subgroupthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in salt form ormetal complex, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, particularly, foradministration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed such as, forexample, water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations that are intended tobe converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin.

The compounds of the present invention may also be administered via oralinhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder, a solution beingpreferred. Any system developed for the delivery of solutions,suspensions or dry powders via oral inhalation or insufflation aresuitable for the administration of the present compounds.

Thus, the present invention also provides a pharmaceutical compositionadapted for administration by inhalation or insufflation through themouth comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. Preferably, the compounds of the present inventionare administered via inhalation of a solution in nebulized oraerosolized doses.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

The compounds of formula (I) show antiviral properties as shown in theexperimental section below. Some of the compounds of formula (I) havealso been tested in an in vivo rat model and showed favourablepharmacokinetic properties. In particular, compounds of formula (I)wherein R⁴ is a phenyl or substituted phenyl group showed goodpharmacokinetic properties.

Viral infections and their associated diseases treatable using thecompounds and methods of the present invention include those infectionsbrought on by HCV and other pathogenic flaviviruses such as Yellowfever, Dengue fever (types 1-4), St. Louis encephalitis, Japaneseencephalitis, Murray valley encephalitis, West Nile virus and Kunjinvirus. The diseases associated with HCV include progressive liverfibrosis, inflammation and necrosis leading to cirrhosis, end-stageliver disease, and HCC; and for the other pathogenic flaviviruses thediseases include yellow fever, dengue fever, hemorrhagic fever andencephalitis.

Due to their antiviral properties, particularly their anti-HCVproperties, the compounds of formula (I) or any subgroup thereof, theirN-oxides, salts, quaternary amines, metal complexes and stereochemicallyisomeric forms, are useful in the treatment of individuals experiencinga viral infection, particularly a HCV infection, and for the prophylaxisof these infections. In general, the compounds of the present inventionmay be useful in the treatment of warm-blooded animals infected withviruses, in particular flaviviruses such as HCV.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines. Said use as a medicine or method oftreatment comprises the systemic administration to viral infectedsubjects or to subjects susceptible to viral infections of an amounteffective to combat the conditions associated with the viral infection,in particular the HCV infection.

The present invention also relates to the use of the present compoundsor any subgroup thereof in the manufacture of a medicament for thetreatment or the prevention of viral infections, particularly HCVinfection.

The present invention furthermore relates to a method of treating awarm-blooded animal infected by a virus, or being at risk of infectionby a virus, in particular by HCV, said method comprising theadministration of an anti-virally effective amount of a compound offormula (I), as specified herein, or of a compound of any of thesubgroups of compounds of formula (I), as specified herein.

The present invention also concerns combinations of a compound offormula (I) or any subgroup thereof, as specified herein with otheranti-HCV agents.

The combination of previously known anti-HCV compound, such as, forinstance, interferon-α (IFN-α), pegylated interferon-α, or ribavirin,and a compound of formula (I) can be used as a medicine in a combinationtherapy. The term “combination therapy” relates to a product containingmandatory (a) a compound of formula (I), and (b) at least one otheranti-HCV compound, as a combined preparation for simultaneous, separateor sequential use in treatment of HCV infections, in particular, in thetreatment of infections with HCV.

Anti-HCV compounds encompass agents selected from HCV polymeraseinhibitors, R1626, R7128, MK-0608, VCH759, VCH916, PF-868554 andGS91-90; NM283, JTK109, JTK003, HCV371, HCV086, HCV796, XTL2125,GSK625433, ANA598, IDX184, MK3281, MK1220, A831, A689, ABT333, HCVproteases (NS2-NS3 and NS3-NS4A) inhibitors, the compounds of WO02/18369(see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line11), BI-1335, TMC435350, VX-950, SCH 503034, MK70009 and ITMN-191;GS9132, TMC493706, BILN-2065, BMS605339, R7227, VX500, inhibitors ofother targets in the HCV life cycle, including helicase, NSSA likeBMS790052 and metalloprotease inhibitors, ISIS-14803; immunomodulatoryagents such as, α-, β-, and γ-interferons, pegylated derivatizedinterferon-α compounds, compounds that stimulate the synthesis ofinterferon in cells, interleukins, Toll like receptor (TLR) agonists,compounds that enhance the development of type 1 helper T cell response,and thymosin; other antiviral agents such as ribavirin, amantadine, andtelbivudine, inhibitors of internal ribosome entry, broad-spectrum viralinhibitors, such as IMPDH inhibitors (e.g., compounds of U.S. Pat. No.5,807,876, U.S. Pat. No. 6,498,178, U.S. Pat. No. 6,344,465, U.S. Pat.No. 6,054,472, WO97/40028, WO98/40381, WO00/56331, and mycophenolic acidand derivatives thereof, and including, but not limited to VX-950,VX-497, VX-148, and/or VX-944); or combinations of any of the above.

Thus, to combat or treat HCV infections, the compounds of formula (I)may be co-administered in combination with for instance, interferon-α(IFN-α), pegylated interferon-α, ribavirin or a combination thereof, aswell as therapeutics based on antibodies targeted against HCV epitopes,small interfering RNA (Si RNA), ribozymes, DNAzymes, antisense RNA,small molecule antagonists of for instance NS3 protease, NS3 helicaseand NS5B polymerase.

The combinations of the present invention may be used as medicaments.Accordingly, the present invention relates to the use of a compound offormula (I) or any subgroup thereof as defined above for the manufactureof a medicament useful for inhibiting HCV activity in a mammal infectedwith HCV viruses, wherein said medicament is used in a combinationtherapy, said combination therapy preferably comprising a compound offormula (I) and at least one other HCV inhibitory compound, e.g. IFN-α,pegylated IFN-α, or ribavirin.

Furthermore, it is known that a large percentage of patients infectedwith human immunodeficiency virus 1 (HIV) are also infected with HCV,i.e. they are HCV/HIV co-infected. HIV infection appears to adverselyaffect all stages of HCV infection, leading to increased viralpersistence and accelerated progression of HCV-related liver disease. Inturn, HCV infection may affect the management of HIV infection,increasing the incidence of liver toxicity caused by antiviralmedications.

The present invention therefore also concerns combinations of a compoundof formula (I) or any subgroup thereof with anti-HIV agents. Also, thecombination of one or more additional anti-HIV compounds and a compoundof formula (I) can be used as a medicine.

The term “combination therapy” also encompasses a product comprising (a)a compound of formula (I), and (b) an anti-HIV compound, and (c)optionally another anti-HCV compound, as a combined preparation forsimultaneous, separate or sequential use in treatment of HCV and HIVinfections, in particular, in the treatment of infections with HCV andHIV.

Thus, the present invention also relates to a product containing (a) acompound of formula (I) or any subgroup thereof, and (b) one or moreadditional anti-HIV compounds, as a combined preparation forsimultaneous, separate or sequential use in anti-HCV and anti-HIVtreatment. The different drugs may be combined in a single preparationtogether with pharmaceutically acceptable carriers. Said other anti-HIVcompounds may be any known antiretroviral compounds such as suramine,pentamidine, thymopentin, castanospermine, dextran (dextran sulfate),foscarnet-sodium (trisodium phosphono formate); nucleoside reversetranscriptase inhibitors (NRTIs), e.g. zidovudine (AZT), didanosine(ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T),emtricitabine (FTC), abacavir (ABC), amdoxovir (DAPD), elvucitabine(ACH-126,443), AVX 754 ((−)-dOTC), fozivudine tidoxil (FZT),phosphazide, HDP-990003, KP-1461, MIV-210, racivir (PSI-5004), UC-781and the like; non-nucleoside reverse transcriptase inhibitors (NNRTIs)such as delavirdine (DLV), efavirenz (EFV), nevirapine (NVP), dapivirine(TMC120), etravirine (TMC125), rilpivirine (TMC278), DPC-082,(+)-Calanolide A, BILR-355, and the like; nucleotide reversetranscriptase inhibitors (NtRTIs), e.g. tenofovir ((R)-PMPA) andtenofovir disoproxil fumarate (TDF), and the like; nucleotide-competingreverse transcriptase inhibitors (NcRTIs), e.g. NcRTI-1 and the like;inhibitors of trans-activating proteins, such as TAT-inhibitors, e.g.RO-5-3335, BI-201, and the like; REV inhibitors; protease inhibitorse.g. ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV),indinavir (IDV), amprenavir (VX-478), TMC126, nelfinavir (AG-1343),atazanavir (BMS 232,632), darunavir (TMC114), fosamprenavir (GW433908 orVX-175), brecanavir (GW-640385, VX-385), P-1946, PL-337, PL-100,tipranavir (PNU-140690), AG-1859, AG-1776, Ro-0334649 and the like;entry inhibitors, which comprise fusion inhibitors (e.g. enfuvirtide(T-20)), attachment inhibitors and co-receptor inhibitors, the lattercomprise the CCRS antagonists (e.g. ancriviroc, CCR5 mAb004, maraviroc(UK-427,857), PRO-140, TAK-220, TAK-652, vicriviroc (SCH-D,SCH-417,690)) and CXR4 antagonists (e.g. AMD-070, KRH-27315), examplesof entry inhibitors are PRO-542, TNX-355, BMS-488,043, BlockAide/CR™, FP21399, hNM01, nonakine, VGV-1; a maturation inhibitor for example isPA-457; inhibitors of the viral integrase e.g. raltegravir (MK-0518),elvitegravir (JTK-303, GS-9137), BMS-538,158; ribozymes;immunomodulators; monoclonal antibodies; gene therapy; vaccines; siRNAs;antisense RNAs; microbicides; Zinc-finger inhibitors.

Therefore, HCV infected patients also suffering from conditionsassociated with HIV or even other pathogenic retroviruses, such as AIDS,AIDS-related complex (ARC), progressive generalized lymphadenopathy(PGL), as well as chronic CNS diseases caused by retroviruses, such as,for example HIV mediated dementia and multiple sclerosis, canconveniently be treated with the present composition.

The compositions may be formulated into suitable pharmaceutical dosageforms such as the dosage forms described above. Each of the activeingredients may be formulated separately and the formulations may beco-administered or one formulation containing both and if desiredfurther active ingredients may be provided.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, as well as any productwhich results, directly or indirectly, from the combination of thespecified ingredients.

The term “therapeutically effective amount” as used herein means thatamount of active compound or component or pharmaceutical agent thatelicits the biological or medicinal response in a tissue, system, animalor human that is being sought, in the light of the present invention, bya researcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease being treated. Sincethe instant invention refers as well to combinations comprising two ormore agents, the “therapeutically effective amount” in the context ofcombinations is also that amount of the agents taken together so thatthe combined effect elicits the desired biological or medicinalresponse. For example, the therapeutically effective amount of acomposition comprising (a) the compound of formula (I) and (b) anotheranti-HCV agent, would be the amount of the compound of formula (I) andthe amount of the other anti-HCV agent that when taken together have acombined effect that is therapeutically effective.

In general, it is contemplated that an antiviral effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

In one embodiment of the present invention there is provided an articleof manufacture comprising a composition effective to treat an HCVinfection or to inhibit the NS5B polymerase of HCV; and packagingmaterial comprising a label which indicates that the composition can beused to treat infection by the hepatitis C virus; wherein thecomposition comprises a compound of the formula (I) or any subgroupthereof, or the combination as described herein.

Another embodiment of the present invention concerns a kit or containercomprising a compound of the formula (I) or any subgroup thereof, in anamount effective for use as a standard or reagent in a test or assay fordetermining the ability of potential pharmaceuticals to inhibit HCV NS5Bpolymerase, HCV growth, or both. This aspect of the invention may findits use in pharmaceutical research programs.

The compounds and combinations of the present invention can be used inhigh-throughput target-analyte assays such as those for measuring theefficacy of said combination in HCV treatment.

EXAMPLES

The following examples are intended to illustrate the present inventionand not to limit it thereto.

Example 1 Synthesis of17-cyclohexyl-18-(furan-3-yl)-1,4,11-triaza-tricyclo-[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(1)

Step A.

Cyclohexanone (18.2 g, 186 mmol) was added to a solution ofindole-6-carboxylic acid 1-1 (10.0 g, 62.0 mmol) in methanol (100 mL).Then, a solution of sodium methoxide (20.4 g, 378.5 mmol) in methanol(50 mL) was added dropwise. The resulting solution was heated to reflux.After 5 days, the reaction mixture was evaporated and ice-cold water(250 mL) was added. The precipitate was filtered off, washed with waterand dried under vacuum to give 12.0 g (80.1%) of the target compoundI-2: m/z=242 (M+H)⁺.

Step B.

A mixture of 1-2 (14.0 g, 58 mmol) and 20% Pd(OH)₂/C (600 mg) inmethanol (50 mL) and THF (50 mL) was shaken in a hydrogenation apparatusunder 55 psi pressure at room temperature for 3 h. The catalyst wasremoved by filtration and washed with methanol. The filtrate wasconcentrated to dryness. The residue was triturated in hexane, then thebeige solid was collected by filtration, washed with hexane and driedunder vacuum to give 12.3 g (87%) of the target product 1-3: m/z=244(M+H)⁺.

Step C.

Thionyl chloride (135 μL, 1.85 mmol) was added to a solution of3-cyclohexylindole-6-carboxylic acid (1-3, 1.80 g, 7.4 mmol) in methanol(20 mL). The resulting solution was heated to reflux for 1 h, thenallowed to cool down to room temperature. The reaction mixture wasconcentrated under vacuum. Then, the residue was partitioned betweenCH₂Cl₂ and ice-cold water, dried and evaporated to give 1.05 g (55.2%)of the target product 1-4: m/z=258 (M+H)⁺.

Step D.

Methyl 3-cyclohexyl-6-indole carboxylate (1-4, 8.00 g, 31.1 mmol) wasdissolved in a mixture of THF (20 mL) and CHCl₃ (20 mL). Then, thesolution was cooled at 0° C. and pyridine tribromide (8.00 g, 31.1 mmol)was added. After 1.5 h at 0° C., the reaction mixture was diluted withCHCl₃ (40 mL), washed with 1N NaHSO₃, saturated NaHCO₃ and brine. Theorganic layer was dried (Na₂SO₄) and evaporated to dryness. Purificationby column chromatography (ethyl acetate/hexane 1:1) afforded 7.70 g(73.7%) of the target compound 1-5: m/z=337 (M+H)⁺.

Step E.

A solution of Na₂CO₃ (1M, 31.2 mmol) was added to a solution of the2-bromoindole 1-5 (5.00 g, 14.8 mmol), 3-furanboronic acid (2.50 g, 22.3mmol), and LiCl (1.26 g, 29.7 mmol) in a mixture of ethanol (50 mL) andtoluene (50 mL). The reaction mixture was degassed with nitrogen. Then,tetrakis(triphenylphosphine)palladium(0) (1.72 g, 1.49 mmol) was added.The resulting reaction mixture was stirred at 80° C. under inertatmosphere. After 12 h, the reaction mixture was allowed to cool down toroom temperature and volatiles were removed under reduced pressure. Theresidue was partitioned between NaHCO₃ 0.5 N and ethyl acetate. Theorganic layer was dried (Na₂SO₄), evaporated and purified by columnchromatography (gradient of ethyl acetate/CH₂Cl₂ 1:9 to 1:1).Crystallization from isopropanol yielded 4.12 g (85.6%) of the targetproduct 1-6: m/z=324 (M+H)⁺.

Step F.

A dispersion of NaH in mineral oil was added at 0° C. to a solution ofthe ester 1-6 and bromoacetic acid methyl ester (615 mg, 4.02 mmol) indry dimethylformamide (DMF; 5 mL). After 10 min at 0° C., the reactionmixture was warmed up to room temperature for 1 h. Then, the solutionwas poured into ice-cold water and extracted with ethyl acetate, dried(Na₂SO₄) and evaporated. The crude material was purified by columnchromatography (ethyl acetate/CH₂Cl₂/heptane, 1:4:5) to give the targetproduct 1-7, which was triturated in ether, filtered and washed withpetroleum ether. The target product 1-7 (1.0 g, 82%) was obtained as ayellowish powder: m/z=396 (M+H)⁺.

Step G.

A solution of lithium hydroxide (1.54 g, 63.1 mmol) in water (50 mL) wasadded to a solution of the diester 1-7 (1.0 g, 2.53 mmol) in methanol(100 mL) and tetrahydro-furan (THF; 50 mL). The resulting solution wasstirred at room temperature for 48 h. Then, volatiles were evaporatedunder reduced pressure. The residue was dissolved in water (100 mL) andthe pH of the solution was adjusted to 3 with a 1N aqueous solution ofHCl. The resulting solution was successively extracted with ethylacetate, dried (Na₂SO₄) and evaporated. The residue was triturated inether, then filtered off to afford 680 mg (73.2%) of the target diacid1-8 as a yellowish powder: m/z=368 (M+H)⁺.

Step H.

2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium (HATU) (466 mg, 1.22 mmol) was addedto a stirred solution of the diacid 1-8 (150 mg, 0.408 mmol) andbut-3-enylamine (116 mg, 1.63 mmol) in DMF (5 mL). Then,diisopropylethylamine (284 μL, 1.63 mmol) was added dropwise. After 12h, the reaction mixture was successively partitioned between ethylacetate and ice-cold water, dried (Na₂SO₄) and evaporated. The residuewas purified by column chromatography (ethyl acetate/hexane 1:1) to give161 mg (83.3%) of the target product 1-9 as a white powder: m/z=474(M+H)⁺.

Step I.

A solution of 1-9 (150 mg, 0.317 mmol) and Hoveyda-Grubbs 1^(st)generation catalyst (19 mg, 0.032 mmol) in degassed dichloroethane (200mL) was heated at 80° C. for 12 h. Then, additional catalyst (20 mg,0.034 mmol) was added and the reaction mixture was heated for another 3h at 80° C. Then, the reaction mixture was concentrated under vacuum andthe residue was purified by column chromatography (gradient CH₂Cl₂/ethylacetate/heptane, 2:2:1 to 0:1:0). Crystallization from ethyl acetateprovided 35 mg (22%) of the target product 1 as a white powder: m/z=446(M+H)⁺.

Example 217-Cyclohexyl-18-(furan-3-yl)-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-13(20),14,16(19),17-tetraene-3,12-dione(2)

A mixture of 1 (30 mg, 0.067 mmol) and 10% Pd/C (20 mg) in methanol (10mL) and THF (10 mL) was shaken in a hydrogenation apparatus under 55 psipressure at room temperature for 1 h. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated todryness. Filtration on silica gel afforded 24 mg (80%) of the targetproduct 2: m/z=448 (M+H)⁺.

Example 3 Preparation of 17-cyclohexyl-18-[4-[2-(4methanesulfonylpiperazin-1-yl)-5-nitrobenzyloxy]phenyl]-1,4,11-triazatricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(3)

Step A.

A solution of 2-chloro-5-nitrobenzoic acid 3-1 (101 mg, 0.503 mmol),N-methyl-sulfonylpiperazine 3-2 (110 mg, 0.673 mmol) and cesiumcarbonate (335 mg, 1.03 mmol) in DMF (5 mL) was heated at 100° C. undernitrogen. After 12 h, the reaction mixture was successively cooled downat room temperature and acidified to pH 5 with an aqueous 6 N solutionof HCl. The precipitate was collected by filtration to give 75 mg(45.3%) of the target product 3-3: m/z=330 (M+H)⁺. On larger scale (4.53g of 3 1) the target product 3-3 was obtained with a yield of 87.1%.

Step B.

A solution of acid 3-3 (508 mg, 1.54 mmol), methyliodide (120 μL, 1.93mmol) and NaHCO₃ (220 mg, 2.61 mmol) in dry DMF (10 mL) was stirred atroom temperature for 12 h. Then, the reaction mixture was diluted withwater (400 mL). The precipitate was collected by filtration, washed withwater and isopropylether, then dried under vacuum to give 491 mg (93%)of the target product 3-4: m/z=344 (M+H)⁺.

Step C.

LiAlH₄ (113 mg, 2.99 mmol) was added at 0° C. under nitrogen to asuspension of the nitro derivative 3-4 (491 mg, 1.43 mmol) in dry THF(20 mL). The resulting orange suspension was stirred at room temperaturefor 3 days. Then, LiAlH₄ (57 mg, 1.45 mmol) was added. The resultingreaction mixture was stirred for an additional 12 h at room temperature.Then, the reaction mixture was successively diluted with ice-cold water,and the pH was adjusted to 5 with acetic acid. The resulting solutionwas extracted with ethyl acetate, dried (Na₂SO₄) and evaporated todryness. The residue was purified by column chromatography (ethylacetate/CH₂Cl₂, 15:85) to give the target product 3-5: m/z=316 (M+H)⁺.

Step D.

A 1 M solution of K₂CO₃ (10 mL) was added to a solution of bromoindole1-5 (1.83 g, 5.43 mmol), 4-benzyloxybenzeneboronic acid (1.86 g, 8.15mmol) and bis(triphenylphosphine)palladium (II) chloride (420 mg, 0.599mmol) in ethanol (20 mL) and toluene (20 mL). The resulting reactionmixture was heated at 80° C. for 12 h. Then, volatiles were evaporatedunder vacuum. The residue was successively partitioned between ethylacetate and diluted NaHCO₃, washed with brine, dried (Na₂SO₄) andevaporated. The residue was triturated in methanol, then filtered off togive 1.55 g (65%) of the target product 3-6: m/z=440 (M+H)⁺.

Step E.

A dispersion of NaH in mineral oil (60%, 180 mg, 4.50 mmol) was added at0° C. to a solution of the ester 3-6 and bromoacetic acid methyl ester(703 mg, 4.59 mmol) in dry DMF (12 mL). After 20 min at 0° C., thereaction mixture was warmed up to room temperature for 1 h. Then, thesolution was poured into ice-cold water (200 mL). The precipitate wasfiltered off, washed with water and petroleum ether to give 1.45 g(80.5%) of the target product 3-7 as a yellow powder: m/z=512 (M+H)⁺.

Step F.

A mixture of 3-7 (1.45 g, 2.84 mmol) and 10% Pd/C (200 mg) in methanol(100 mL) and THF (100 mL) was shaken in a hydrogenation apparatus under55 psi pressure at room temperature for 2 h. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated todryness. Filtration on silica gel afforded 1.11 g (92%) of the targetproduct 3-8: m/z=422 (M+H)⁺.

Step G.

DIAD (100 μL, 0.507 mmol) was added at 0° C. under nitrogen to a stirredsolution of sulfonamide 3-5 (107 mg, 0.338 mmol), indole 3-8 (139 mg,0.328 mmol) and triphenylphosphine (162 mg, 0.618 mmol) in dry THF (10mL). Then, the reaction mixture was allowed to warm up to roomtemperature. After 12 h, volatiles were evaporated and the residue waspurified by column chromatography (ethyl acetate/CH₂Cl₂, 15:85) to give138 mg of the desired product 3-9: m/z=719 (M+H)⁺.

Step H.

Intermediate 3-10 was prepared in 99.9% yield by adding a solution oflithium hydroxide in water to 3-9 in methanol and THF. The resultingsolution was stirred at room temperature for 48 h. Then, volatiles wereevaporated under reduced pressure. The residue was dissolved in waterand the pH of the solution was adjusted to 3 with a 1 N aqueous solutionof HCl. The resulting solution was successively extracted with ethylacetate, dried (Na₂SO₄) and evaporated. The residue was triturated inether, then filtered off to afford the target diacid 3-10: m/z=691(M+H)⁺.

Step I.

Intermediate 3-11 was prepared in 69.7% yield by adding HATU to astirred solution of the diacid 3-10 and but-3-enylamine in DMF. Then,diisopropylethylamine was added dropwise. After 12 h, the reactionmixture was successively partitioned between ethyl acetate and ice-coldwater, dried (Na₂SO₄) and evaporated. The residue was purified by columnchromatography (ethyl acetate/hexane 1:1) to give the target product3-11: m/z=797 (M+H)⁺.

Step J.

Intermediate 3 was prepared in 70% yield by heating a solution of 3-11and Hoveyda-Grubbs 1^(st) generation catalyst in degassed dichloroethaneat 80° C. for 12 h. Then, additional catalyst was added and the reactionmixture was heated for another 3 h at 80° C. Next, the reaction mixturewas concentrated under vacuum and the residue was purified by columnchromatography (gradient CH₂Cl₂/ethyl acetate/heptane, 2:2:1 to 0:1:0).Crystallization from ethyl acetate provided the target product 3:m/z=769 (M+H)⁺.

Example 4 17-cyclohexyl-18-[4-[2-(4methanesulfonylpiperazin-1-yl)-5-amino-benzyloxy]phenyl]-1,4,11-triazatricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione (4)

Tin(II) chloride dihydrate (400 mg, 1.77 mmol) was added to a solutionof 3 (55 mg, 0.0715 mmol) in THF (1 mL) and ethanol (1.5 mL). Thereaction mixture was heated at reflux for 3 days, then allowed to cooldown to room temperature. Then, volatiles were evaporated under vacuumand the residue was successively partitioned between a diluted solutionof NaHCO₃ and ethyl acetate, dried (Na₂SO₄) and evaporated. Purificationby column chromatography (CH₂Cl₂/methanol, 97.5:2.5) afforded the titlecompound 4 as a yellowish powder: m/z=740 (M+H)⁺.

Example 5 17-cyclohexyl-18-[4-[2-(4methanesulfonylpiperazin-1-yl)-5-acetylamino-benzyloxy]phenyl]-1,4,11-triazatricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(5)

Acetyl chloride (4 μL, 0.057 mmol) was added under nitrogen to asolution of 4 (38 mg, 0.051 mmol) and N,N′-diisopropylethylamine (DIPEA;8.7 μL, 0.062 mmol) in CHCl₃ (2 mL). After 12 h, the reaction mixturewas successively partitioned between CHCl₃ and diluted NaHCO₃, dried(Na₂SO₄) and evaporated. The residue was purified by columnchromatography to give 25 mg (61.7%) of the title product 5 as a whitepowder: m/z=782 (M+H)⁺. NMR (DMSO-d6): δ (ppm) 1.19-1.35 (m, 4H),1.68-1.77 (m, 4H), 1.90 (m, 2H), 2.02 (s, 3H, COCH₃), 2.18 (m, 2H), 2.33(m, 2H), 2.50 (m, 1H), 2.75 (m, 2H), 2.92 (s, 3H, SO₂CH₃), 2.96 (m, 2H),3.33 (m, 8H), 4.43 (s, 2H, CH₂CONH), 5.22 (s, 2H, OCH₂), 5.35 (m, 1H),5.53 (m, 1H), 7.17-7.20 (m, 3H), 7.39-7.60 (m, 5H), 7.69-7.79 (m, 2H),7.86 (broad s, 1H, NH), 8.33+8.56 (m, 1H, NH), 9.95 (s, 1H, NH).

Example 6N-[3-[4-(17-cyclohexyl-3,12-dioxo-1,4,11-triazatricyclo[11.5.2.0^(16,19)]icosa-13(20),14,16(19),17-tetraen-18-yl)phenoxymethyl]-4-(4-methanesulfonylpiperazin-1-yl)-phenyl]acetamide(6)

The title product 6 was prepared by shaking a mixture of 5, 10% Pd/C inmethanol, and THF in a hydrogenation apparatus under 55 psi pressure atroom temperature for 1 h. The catalyst was removed by filtration andwashed with methanol. The filtrate was concentrated to dryness.Filtration on silica gel afforded the target product 6: m/z=784 (M+H)⁺.

Example 718-(4-benzyloxyphenyl)-17-cyclohexyl-1,4,11-triazatricyclo[11.5.2.0^(16,19)]-icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(7)

Step A.

Intermediate 7-1 was prepared in 90% yield from 1-5 by adding adispersion of NaH in mineral oil at 0° C. to a solution of the ester 1-5and bromoacetic acid methyl ester in dry DMF. After 10 min at 0° C., thereaction mixture was warmed up to room temperature for 1 h. Then, thesolution was poured into ice-cold water and extracted with ethylacetate, dried (Na₂SO₄) and evaporated. The crude material was purifiedby column chromatography (ethyl acetate/CH₂Cl₂/heptane, 1:4:5) to givethe target product 7-1 which was triturated in ether, filtered andwashed with petroleum ether: m/z=409 (M+H)⁺.

Step B.

Intermediate 7-2 was prepared in 88% yield from 7-1 by adding a solutionof lithium hydroxide in water to a solution of diester 7-1 in methanoland THF. The resulting solution was stirred at room temperature for 48h. Then, volatiles were evaporated under reduced pressure. The residuewas dissolved in water and the pH of the solution was adjusted to 3 witha 1N aqueous solution of HCl. The resulting solution was successivelyextracted with ethyl acetate, dried (Na₂SO₄) and evaporated. The residuewas triturated in ether, then filtered off to afford the target diacid7-2: m/z=381 (M+H)⁺.

Step C.

Intermediate 7-3 was prepared in 78% yield from 7-2 by adding HATU to astirred solution of the diacid 7-2 and but-3-enylamine in DMF. Then,diisopropylethylamine was added dropwise. After 12 h, the reactionmixture was successively partitioned between ethyl acetate and ice-coldwater, dried (Na₂SO₄) and evaporated. The residue was purified by columnchromatography (ethyl acetate/hexane 1:1) to give the target product7-3: m/z=487 (M+H)⁺.

Step D.

Intermediate 7-4 was prepared in 58% yield from 7-3 by heating asolution of 7-3 and Hoveyda-Grubbs 1^(st) generation catalyst indegassed dichloroethane at 80° C. for 12 h.

Then, additional catalyst was added and the reaction mixture was heatedfor another 3 h at 80° C. Next, the reaction mixture was concentratedunder vacuum and the residue was purified by column chromatography(gradient CH₂Cl₂/ethyl acetate/heptane, 2:2:1 to 0:1:0). Crystallizationfrom ethyl acetate provided the target product 7-4: m/z=459 (M+H)⁺.

Step E.

The target product 7 was prepared in 54% yield from 7-4 following theprocedure reported for the synthesis of intermediate 3-6: m/z=562(M+H)⁺.

Example 818-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-17-cyclohexyl-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-13(20),14,16(19),17-tetraene-3,12-dione(9)

Step A.

Intermediate 8 was prepared in 95% yield from 7 by shaking a mixture of7, 10% Pd/C (20 mg) in methanol, and THF in a hydrogenation apparatusunder 55 psi pressure at room temperature for 1 h. The catalyst wasremoved by filtration and washed with methanol. The filtrate wasconcentrated to dryness. Filtration on silica gel afforded the targetproduct 8: m/z=474 (M+H)⁺.

Step B.

A solution of the phenol 8 (20 mg, 0.042 mmol),2-bromo-5-methoxybenzylbromide (13 mg, 0.0465 mmol) and potassiumcarbonate (6.42 mg, 0.0465 mmol) in DMF (2 mL) was heated under nitrogenat 80° C. After 12 h, the reaction mixture was allowed to cool down toroom temperature. The resulting solution was acidified to pH 4 with a 1N aqueous solution of HCl and the precipitate was collected byfiltration, then dried under high vacuum pump. Purification by columnchromatography (CH₂Cl₂, methanol, 96.5:3.5) afforded 93 mg (51%) of thetarget product 9 as a white powder: m/z=673 (M+H)⁺.

Example 918-[4-(4′-chloro-4-methoxybiphenyl-2-ylmethoxy)phenyl]-17-cyclohexyl-1,4,11-triazatricyclo[11.5.2.0^(16,19)]icosa-13(20),14,16(19),17-tetraene-3,12-dione(10)

A saturated solution of NaHCO₃ (1 mL) was added to a solution of 9 (20mg, 0.029 mmol), 4-chlorobenzeneboronic acid (11 mg, 0.068 mmol) andbis(triphenyl-phosphine)palladium (II) chloride (4 mg, 0.0063 mmol) indimethoxyethane (DME; 6 mL). The resulting solution was heated at 73° C.for 8 h. Then, the reaction mixture was successively cooled down to roomtemperature, partitioned between water and ethyl acetate, dried (Na₂SO₄)and evaporated. Purification by column chromatography (CH₂Cl₂/methanol,97:3) afforded the target product contaminated with impurities. Theproduct was further purified by trituration in methanol, then filteredoff to give the target product 10: m/z=704 (M+H)⁺. NMR (DMSO-d6): δ(ppm) 1.23-1.33 (m, 6H), 1.42-1.53 (m, 8H), 1.67-1.77 (m, 2H), 1.87-2.02(m, 2H), 2.80 (m, 1H, CH cyclohexyl), 3.15 (m, 4H, 2×CH ₂NHCO), 3.83 (s,3H, OCH₃), 4.44 (s, 2H, CH ₂CONH), 5.00 (s, 2H, CH₂O), 7.04-7.09 (m,3H), 7.23 (d, J=2.6 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.40-7.47 (m, 7H),7.76 (d, J=8.4 Hz, 1H), 7.93 (s, 1H), 8.30 (broad s, 1H, NH), 8.51(broad s, 1H, NH).

Example 1017-Cyclohexyl-18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione (11)

Step A.

To a solution of 2-fluoro-5-nitrobenzoic acid 10-1 (5.22 g, 28.2 mmol)in methanol (30 mL) was added chlorotrimethylsilane 10-2 (6.00 g, 1.96eq.). The reaction mixture was stirred under reflux during 16 h, thencooled down to room temperature, concentrated and the resultingprecipitate was filtered off, washed with a small quantity of methanol,then heptane, to provide 4.36 g (78% yield) of 2-fluoro-5-nitro-benzoicacid methyl ester 10-3 as a white powder; m/z=200 (M+H)⁺.

Step B.

To a solution of 10-3 (4.36 g, 22 mmol) in dimethylsulfoxide (DMSO; 30mL) were added morpholine (2.5 g, 1.3 eq) and potassium carbonate (3.98g, 1.3 eq). The reaction mixture was heated at 80° C. during 1 h, thencooled down to room temperature, poured into 300 mL of water and theresulting yellow solid was filtered off, washed with a bit of water thenpetroleum ether, to afford 5.8 g (98% yield) of2-morpholin-4-yl-5-nitro-benzoic acid methyl ester 10-4; m/z=267 (M+H)⁺.

Step C.

A solution of 10-4 (5.72 g, 21.5 mmol) in methanol was catalyticallyhydrogenated with Pd/C, then filtered and concentrated to dryness toafford the desired product 5-amino-2-morpholin-4-yl-benzoic acid methylester 10-5 (4.94 g, 97% yield); m/z=237 (M+H)⁺.

Step D.

To an ice-cooled suspension of 10-5 (4.94 g, 21 mmol) in THF (100 mL),was added LiAlH₄ (4.0 g, 5 eq) in one portion under N₂. The reactionmixture was allowed to warm up to room temperature and was stirredduring 16 h. The reaction mixture was then poured into ice-water and THFwas evaporated under reduced pressure. The aqueous layer was acidifiedwith acetic acid until pH 5 and extracted several times with ethylacetate. The combined organic layers were then dried over sodiumsulfate, filtered and concentrated to dryness, to afford 3.5 g (80%yield) of the desired product (5-amino-2-morpholin-4-yl-phenyl)-methanol10-6; m/z=209 (M+H)⁺.

Step E.

To a mixture of 10-6 (3.22 g, 15.5 mmol), sodium acetate (13.44 g, 10.6eq) and acetic acid (7.80 g, 8.40 eq) in THF, at 0° C., was added slowly4-chlorobutyryl chloride (5.04 g, 2.2 eq). The ice-bath was then removedand the reaction mixture was stirred at room temperature for 4 h, thendiluted with water. The organic layer was separated, washed with asaturated NaHCO₃ aq. solution, dried with sodium sulfate, filtered andconcentrated to dryness to give 4.84 g (quantitative yield) of thedesired product4-chloro-N-(3-hydroxymethyl-4-morpholin-4-yl-phenyl)-butyramide 10-7;m/z=313 (M+H)⁺.

Step F.

To a solution of 10-7 (4.84 g, 15.47 mmol) in ethanol (50 mL) was addedKOH (3.47 g, 4 eq) dissolved in water (50 mL). The reaction mixture washeated at 80° C. during 2 h, then ethanol was evaporated under reducedpressure. The aqueous layer was diluted with water (100 mL), acidifiedwith HCl 1M until pH 3, and extracted with CH₂Cl₂ (3 times). Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated to dryness. The residue was redissolved in a minimum amountof CH₂Cl₂ and extracted with isopropylether to remove impurities. Theisopropylether solution was then concentrated and the residue trituratedin ether, then filtered off, to afford 2.27 g (53% yield) of the desiredproduct 1-(3-hydroxymethyl-4-morpholin-4-yl-phenyl)-pyrrolidin-2-one10-8 as a beige solid; m/z=277 (M+H)⁺.

Step G.

Intermediate3-cyclohexyl-1-methoxycarbonylmethyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole-6-carboxylicacid methyl ester 10-9 was synthesized in 76% yield from intermediate3-8, following the procedure reported for the synthesis of intermediate3-9 and using 10-8 instead of intermediate 3-5; m/z=680 (M+H)⁺.

Step H.

To a solution of intermediate 10-9 (260 mg, 0.191 mmol) in THF/methanol1:1 (10 mL) was added NaOH (1.00 g, 131 eq) dissolved in water (2 mL).The reaction mixture was stirred at room temperature until completion,then acidified with HCl 3 M until pH 4, diluted with water andconcentrated under reduced pressure to remove organic solvents. Theresulting aqueous layer was subsequently extracted with THF and theorganic layer was separated, dried with sodium sulfate, filtered andconcentrated to dryness to afford 150 mg (60% yield) of the desiredintermediate[1-carboxymethyl-3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole]-6-carboxylicacid 10-10. This intermediate was used without further purification inthe next step; m/z=652 (M+H)⁺.

Step I.

The target product1-but-3-enylcarbamoylmethyl-3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole-6-carboxylicacid but-3-enylamide 10-11 was synthesized in 38% yield, following theprocedure reported for the synthesis of intermediate 3-11 and usingintermediate 10-10 instead of intermediate 3-10; m/z=758 (M+H)⁺.

Step J.

The target product17-cyclohexyl-18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione 11 was synthesized in 25% yield,following the procedure reported for the synthesis of compound 3 andusing intermediate 10-11 instead of intermediate 3-11; m/z=730 (M+H)⁺.

Example 11 17-Cyclohexyl-18-[4-[2-(4methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione (12)

Step A.

A solution of 3-4 (5.72 g, 16.66 mmol) in methanol was catalyticallyhydrogenated with Pd/C, then filtered and concentrated to dryness toafford the desired product5-amino-2-(4-methanesulfonyl-piperazin-1-yl)-benzoic acid methyl ester11-1 (5.15 g, 99% yield); m/z=314 (M+H)⁺.

Step B.

To an ice-cooled suspension of5-amino-2-(4-methanesulfonyl-piperazin-1-yl)-benzoic acid methyl ester11-1 (4.63 g, 14.78 mmol) in THF (100 mL), was added LiAlH₄ (2.92 g, 5.2eq) in one portion under N₂. The reaction mixture was allowed to warm upto room temperature and was stirred during 16 h. The reaction mixturewas then poured into ice-water and THF was evaporated under reducedpressure. The aqueous layer was acidified with acetic acid until pH 5and extracted several times with ethyl acetate. The combined organiclayers were then dried over sodium sulfate, filtered and concentrated todryness, to afford 4.22 g (57% yield) of the desired product[5-amino-2-(4-methane-sulfonyl-piperazin-1-yl)-phenyl]-methanol 11-2;m/z=286 (M+H)⁺.

Step C.

To a mixture of 11-2 (1.0 g, 3.51 mmol), sodium acetate (2.14 g, 7.4 eq)and acetic acid (2.1 g, 10 eq) in dry THF (20 mL), at 0° C., was addedslowly 4-chlorobutyryl chloride (1.07 g, 2.1 eq). The ice-bath was thenremoved and the reaction mixture was stirred at room temperature for 4h, then diluted with water. The aqueous layer was several timesextracted with CH₂Cl₂ and the combined organic layers were washed with asaturated NaHCO₃ aq. solution, dried with sodium sulfate, filtered andconcentrated to dryness to give 1.36 g (quantitative yield) of thedesired product4-chloro-N-[3-hydroxymethyl-4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-butyramide11-3; m/z=390 (M+H)⁺.

Step D.

To a solution of 11-3 (1.37 g, 3.51 mmol) in ethanol (30 mL) was addedKOH (0.804 g, 4 eq) dissolved in water (30 mL). The reaction mixture washeated at 80° C. for 2 h, then ethanol was evaporated under reducedpressure. The aqueous layer was diluted with water (100 mL) andacidified with HCl 1 M until pH 3. The resulting brown precipitate wasfiltered off, washed with water then petroleum ether and dried in vacuoto afford 873 mg (60% yield) of the desired product1-[3-Hydroxymethyl-4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-pyrrolidin-2-one11-4; m/z=354 (M+H)⁺.

Step E.

The target product3-cyclohexyl-2-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1-methoxycarbonylmethyl-1H-indole-6-carboxylicacid methyl ester 11-5 was synthesized in 57% yield from intermediate3-8, following the procedure reported for the synthesis of intermediate3-9 and using 11-4 instead of intermediate 1-16; m/z=757 (M+H)⁺.

Step F.

To a solution of intermediate 11-5 (291 mg, 0.385 mmol) in THF/methanol1:1 (10 mL) was added NaOH (1.00 g, 32 eq) dissolved in water (5 mL).The reaction mixture was stirred at room temperature until completion,then was acidified with HCl 3 M until pH 4, diluted with water andconcentrated under reduced pressure to remove organic solvents. Theresulting aqueous layer was subsequently extracted with a mixture ofethyl acetate and THF and the organic layer was separated, dried withsodium sulfate, filtered and concentrated. The residue was triturated inpetroleum ether and filtered off to afford 280 mg (99% yield) of thedesired intermediate[1-carboxy-methyl-3-cyclohexyl-2-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole]-6-carboxylicacid 11-6; m/z=729 (M+H)⁺.

Step G.

The target product1-but-3-enylcarbamoylmethyl-3-cyclohexyl-2-[4-[2-(4-methane-sulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole-6-carboxylicacid but-3-enylamide 11-7 was synthesized in 87% yield, following theprocedure reported for the synthesis of intermediate 3-11 and usingintermediate 11-6 instead of intermediate 3-10; m/z=836 (M+H)⁺.

Step H.

The target product17-cyclohexyl-18-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione12 was synthesized in 32% yield, following the procedure reported forthe synthesis of compound 3 and using intermediate 11-7 instead ofintermediate 3-11; m/z=808 (M+H)⁺. NMR (DMSO-d6): δ (ppm) 1.21-1.27 (m,4H, cyclohexyl), 1.66-1.94 (m, 6H, cyclohexyl), 2.06 (qt, J=7.6 Hz, 2H,CH₂ pyrrolidinone), 2.30 (m, 4H, 2×CH ₂CH═CH), 2.48 (m, 2H, CH₂pyrrolidinone), 2.60 (m, 1H, CH cyclohexyl), 2.92 (s, 3H, SO₂CH₃), 2.99(m, 4H, piperidine), 3.28 (m, 4H, piperidine), 3.36 (m, 2H, CH ₂NHCO),3.43 (m, 2H, CH ₂NHCO), 3.82 (t, J=7.1 Hz, 2H, CH₂ pyrrolidinone), 4.39(s, 2H, CH ₂CONH), 5.23 (s, 2H, CH₂O), 5.37 (m, 1H, CH═CH), 5.46 (m, 1H,CH═CH), 7.21 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.58 (dd, J=2.6 Hz, 8.7 Hz, 1H), 7.67(s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.86 (d, J=2.6 Hz, 1H), 8.27 (m, 1H,NH), 8.46 (broad t, J=5.9 Hz, NH).

Example 1217-Cyclohexyl-18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-10,10-dioxo-10λ⁶-thia-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(13)

Step A.

To an ice-cooled solution of intermediate 10-9 (1.02 g, 1.50 mmol) inTHF/methanol 1:1 (20 mL) was added LiOH (40 mg, 1.1 eq) dissolved inwater (2 mL). The reaction mixture was stirred at 0° C. during 5 h, thendiluted with water, acidified with HCl 1 M until pH 4, concentratedunder reduced pressure to remove organic solvents and extracted with amixture of ethyl acetate and THF. The organic layer was separated, driedover sodium sulfate, filtered and concentrated. The obtained residue wastriturated in petroleum ether to give 746 mg (73% yield) of the desiredproduct[1-carboxymethyl-3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole]-6-carboxylicacid methyl ester 12-2 as a slightly yellow powder; m/z=666 (M+H)⁺.

Step B.

To a solution of intermediate 12-2 (476 mg, 0.716 mmol) and HATU (390mg, 1.4 eq) in dry DMF (7 mL), under N₂, were added but-3-enylamine (68mg, 1.35 eq) and Hunig's base (145 mg, 1.5 eq) at room temperature. Thereaction mixture was stirred at room temperature until completion, thenwas poured into ice-water (150 mL) and the resulting white precipitatewas filtered off, washed with a small amount of water then petroleumether, to give 447 mg (87% yield) of the desired intermediate[1-(3-butenyl-carbamoylmethyl)-3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole]-6-carboxylicacid methyl ester 12-3; m/z=719 (M+H)⁺.

Step C.

To a solution of intermediate 12-3 (447 mg, 0.622 mmol) in THF/methanol1:1 (20 mL) was added NaOH (1.24 g, 50 eq) dissolved in water (10 mL).The reaction mixture was stirred at room temperature until completion,then was acidified with HCl 3 M until pH 4, diluted with water andconcentrated under reduced pressure to get rid of the organic solvents.After vigorous stirring, a yellow precipitate appeared in the aqueouslayer; this was filtered off and washed with a bit of petroleum ether toafford 438 mg (quantitative yield) of the desired intermediate[1-but-3-enylcarbamoylmethyl-3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole]-6-carboxylicacid 12-4; m/z=705 (M+H)⁺.

Step D.

To a solution of intermediate 12-4 (438 mg, 0.622 mmol) andprop-2-ene-1-sulfon-amide (151 mg, 2 eq), synthesized as described inJournal of Enzyme Inhibition, 16(6), 475, 2001, in dry DMF (10 mL), wereadded 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDCI; 193 mg, 2eq) and 4-dimethylaminopyridine (DMAP; 152 mg, 2 eq) at roomtemperature, under N₂. After completion, the reaction mixture was pouredinto 200 mL of brine, and extracted with a mixture of ethyl acetate andTHF (several times). The combined organic layers were dried over sodiumsulfate, filtered and concentrated. The obtained residue was trituratedin diethylether and filtered off to afford 436 mg (87% yield) of thedesired productN-but-3-enyl-2-[3-cyclohexyl-2-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-6-(prop-2-ene-1-sulfonylaminocarbonyl)-indol-1-yl]-acetamide12-5 as an off-white solid; m/z=809 (M+H)⁺.

Step E.

The target product17-cyclohexyl-18-[4-[2-morpholin-4-yl-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-10,10-dioxo-10λ⁶-thia-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione 13 wassynthesized in 5% yield from intermediate 12-5, following the procedurereported for the synthesis of compound 3 and using Hoveyda-Grubbs 2^(nd)generation catalyst instead of the 1^(st) generation catalyst; m/z=780(M+H)⁺.

Example 13 17-Cyclohexyl-18-[4-[2-(4methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-10,10-dioxo-10λ⁶-thia-1,4,11-triaza-tricyclo-[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(14)

Step A.

To an ice-cooled solution of intermediate 11-5 (0.606 g, 0.801 mmol) inTHF/methanol 1:1 (20 mL) was added LiOH (21 mg, 1.1 eq) dissolved inwater (2 mL). The reaction mixture was stirred at 0° C. during 5 h, thendiluted with water, acidified with HCl 1 M until pH 4, and concentratedunder reduced pressure to remove organic solvents. The resulting yellowprecipitate was collected by filtration and washed with water andpetroleum ether to give 575 mg (97% yield) of the desired product[1-carboxymethyl-3-cyclohexyl-2-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole]-6-carboxylicacid methyl ester 13-1; m/z=743 (M+H)⁺.

Step B.

The target product1-(but-3-enyl-carbamoyl-methyl)-3-cyclohexyl-2-[4-[2-(4-methane-sulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole-6-carboxylicacid methyl ester 13-2 was obtained in 83% yield as a white powder,following the procedure reported for the synthesis of compound 12-3 andusing intermediate 13-1 instead of intermediate 12-2; m/z=796 (M+H)⁺.

Step C.

The target product1-(but-3-enyl-carbamoyl-methyl)-3-cyclohexyl-2-[4-[2-(4-methane-sulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1H-indole-6-carboxylicacid 13-3 was obtained in 99% yield as a yellow powder, following theprocedure reported for the synthesis of compound 12-4 and usingintermediate 13-2 instead of intermediate 12-3; m/z=782 (M+H)⁺.

Step D.

The target productN-but-3-enyl-2-[3-cyclohexyl-2-[4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-6-(prop-2-ene-1-sulfonylaminocarbonyl)-indol-1-yl]-acetamide13-4 was obtained in 84% yield as a yellow powder, following theprocedure reported for the synthesis of compound 12-5 and usingintermediate 13-3 instead of intermediate 12-4; m/z=886 (M+H)⁺.

Step E.

The target product 14 was obtained in 1% yield as a gray powder,following the procedure reported for the synthesis of compound 13 andusing intermediate 13-4 instead of intermediate 12-5; m/z=858 (M+H)⁺.NMR (DMSO-d6): δ (ppm) 1.12-1.35 (m, 4H, cyclohexyl), 1.65-1.77 (m, 4H,cyclohexyl), 1.86-1.95 (m, 2H, cyclohexyl), 2.06 (qt, J=7.4 Hz, 2H,CH₂-pyrrolidinone), 2.31 (m, 2H, CH ₂CH═CH), 2.48 (m, 2H,CH₂-pyrrolidinone), 2.57 (m, 1H, CH cyclohexyl), 2.90 (s, 3H, SO₂CH₃),2.99 (m, 4H, piperidine), 3.22 (m, 2H, CH ₂NHCO), 3.29 (m, 4H,piperidine), 3.40 (m, 2H, CH₂SO₂), 3.82 (t, J=7.1 Hz, 2H,CH₂-pyrrolidinone), 4.38 (s, 2H, CH ₂CONH), 5.22 (s, 2H, CH₂O), 5.61 (m,2H, CH═CH), 7.18 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.44 (d,J=8.5 Hz, 2H), 7.50 (d, J=8.35 Hz, 1H), 7.59 (dd, J=2.5 Hz, 8.7 Hz, 1H),7.63 (d, J=8.36 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.96 (s, 1H), 8.53(broad t, J=4.9 Hz, 1H, NHCO).

Example 1417-Cyclohexyl-18-[2-fluoro-4-[2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy]-phenyl]-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(15)

Step A:

Intermediate3-cyclohexyl-2-(2-fluoro-4-hydroxy-phenyl)-1-methoxycarbonylmethyl-1H-indole-6-carboxylicacid methyl ester 14-1 was synthesized following the steps D, E and F ofexample 3, starting from bromoindole 1-5 and4-benzyloxy-2-fluorophenyl-boronic acid instead of4-benzyloxybenzeneboronic acid and was obtained in 73% overall yield asa yellow solid; m/z=440 (M+H)⁺.

Step B.

The target product 15 was synthesized following the steps E, F, G and Hof example 11, starting from 11-4 and 14-1 instead of intermediate 3-8,and was obtained as an off-white solid; m/z=826 (M+H)⁺.

Example 15 Synthesis of18-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-17-cyclohexyl-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(16)

Step A.

A mixture of 6-bromo-2-(4′-chloro-4-methoxy-biphenyl-2-yl)-quinoline(200 mg, 0.473 mmol, synthesized as reported in WO2006/076529),bis(neopentylglycolato)-diboron (127 mg, 1.2 eq), potassium acetate (90mg, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.11 eq) in DMSOwas stirred at 50° C. under N₂ during 3 h. The reaction mixture was thendiluted with ethyl acetate, washed with a NaHCO₃ solution (5 M) and withbrine, then dried over Na₂SO₄, filtered and concentrated. The residuewas purified by preparative TLC to afford 150 mg (70%) of2-(4′-chloro-4-methoxy-biphenyl-2-yl)-6-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-quinoline15-1; m/z=458 (M+H⁺).

Step B.

A mixture of intermediate 15-1 (150 mg, 0.328 mmol), intermediate 1-5(110 mg, 1 eq), NaHCO₃ (55 mg, 2 eq) andTetrakis(triphenylphosphine)palladium(0) (0.11 eq) in toluene wasstirred at 80° C. under N₂ overnight. The reaction mixture was thenconcentrated, redissolved with ethyl acetate, washed with aNaHCO₃-solution (5 M) and with brine, then dried over Na₂SO₄, filteredand concentrated. The residue was purified by preparative TLC to afford100 mg (50%) of2-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1H-indole-6-carboxylicacid methyl ester 15-2; m/z=601 (M+H⁺).

Step C.

To a mixture of intermediate 15-2 (1.024 g, 1.7 mmol) andbromomethylacetate (388 mg, 1.5 eq) in dry DMF (30 mL) was added NaH(60% dispersion in mineral oil, 122 mg, 1.8 eq) at 0° C. After stirringfor 20 min at this temperature, the reaction mixture was warmed up toroom temperature. After 24 h, the reaction mixture was poured into 300mL of ice-cold water. The formed yellow solid was filtered off, washedwith petroleum ether and purified by column chromatography (CH₂Cl₂) togive 450 mg (39%) of2-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1-methoxycarbonylmethyl-1H-indole-6-carboxylicacid methyl ester 15-3; m/z=674 (M+H⁺).

Step D.

To a solution of intermediate 15-3 (450 mg, 0.669 mmol) in THF/methanol(1:1, 20 mL) was added a solution of LiOH (1.69 g, 59 eq) in water (10mL) dropwise. The reaction mixture was stirred at room temperature untilcompletion (48 h), then concentrated under reduced pressure, dilutedwith water, acidified with HCl 6 M until pH 3, extracted with ethylacetate, dried over Na₂SO₄, filtered and evaporated to dryness to afford429 mg (99%) of the desired bis-carboxylic acid intermediate as a yellowsolid, which was used without any further purification in the next step;m/z=691 (M+H⁺).

A mixture of the previous intermediate (350 mg, 0.544 mmol), HATU (641mg, 3.1 eq), But-3-enylamine (86 mg, 2.23 eq) and Hunig's base (282 mg,4 eq) in dry DMF (10 mL) was stirred at room temperature under N₂. After18 h, the reaction mixture was poured into water and the yellowprecipitate was filtered off, washed with a bit of water then petroleumether, to afford 300 mg (73%) of1-but-3-enylcarbamoyl-methyl-2-[2-(4′-chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1H-indole-6-carboxylicacid but-3-enylamide 15-4, which was used without any furtherpurification in the next step; m/z=752 (M+H⁺).

Step E.

A solution of intermediate 15-4 (297 mg, 0.396 mmol) in dichloroethene(DCE; 300 mL) was bubbled through with N₂ during 2 h. Hoveyda-Grubbs1^(st) generation catalyst (101 mg, 0.42 eq) was then added and thereaction mixture was heated at 80° C. under N₂ overnight. The reactionmixture was then concentrated under reduced pressure and purified byflash chromatography (CH₂Cl₂/methanol 97.5:2.5) to afford 87 mg (30%) ofthe desired product 16; m/z=724 (M+H⁺), NMR (DMSO-d6): δ (ppm) 1.18-1.34(m, 3H), 1.65 (m, 1H), 1.75 (m, 4H), 1.92 (m, 2H), 2.19 (m, 2H), 2.33(m, 2H), 2.67 (m, 1H), 3.25 (m, 2H), 3.44 (m, 2H), 3.88 (s, 3H, OMe),4.47+4.50 (s, 2H, 0.2/0.8), 5.36 (m, 1H), 5.53 (m, 1H), 7.10 (d, J=8.4Hz, 1H), 7.16 (m, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H),7.32 (d, J=8.4 Hz, 1H), 7.42+7.57 (t, J=5.6 Hz, NH), 7.43 (d, J=8.4 Hz,1H), 7.49 (d, J=8.4 Hz, 1H), 7.74+7.92 (s, 1H, 0.2/0.8), 7.84 (d, J=8.4Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 8.08+8.143 (s, 1H, 0.2/0.8), 8.17 (d,J=8.4 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.30+8.50 (m, 1H, NH).

Example 16 Synthesis of17-Cyclohexyl-18-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione (17)

Step A.

A mixture of intermediate 1-5 (4.02 g, 12 mmol),2-(2,4-dimethyl-thiazol-5-yl)-quinoline-6-boronic acid 16-1 (4.58 g,1.19 eq, synthesized as described in WO2006/076529), K₂CO₃ (5.13 g, 3.1eq) and dichloro-bis(triphenylphosphino)-Pd(II) (0.86 g, 0.10 eq) inethanol/toluene (1:1, 80 mL) was stirred at room temperature under N₂overnight. After concentration under reduced pressure, the reactionmixture was redissolved in ethyl acetate and washed with a 5 M NaHCO₃solution. The obtained yellow precipitate was filtered off, washed withwater, then isopropanol to give 4.13 g (67%) of3-Cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole-6-carboxylicacid methyl ester 16-2 as a yellow solid; m/z=496 (M+H⁺).

Step B.

Intermediate 16-3 was synthesized following the procedure reported inthe step C of the synthesis of example 15, starting from intermediate16-2 (1.134 g, 2.29 mmol) instead of 15-2 and yielding 1.3 g (100%) ofthe pure product3-cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1-methoxycarbonylmethyl-1H-indole-6-carboxylicacid methyl ester 16-3 as a white solid; m/z=568 (M+H⁺).

Step C.

Intermediate 16-4 was synthesized following the procedure reported instep D of the synthesis of example 15, starting from 16-3 (0.52 g, 0.917mmol) instead of 15-3 and yielding 0.5 g (69%) of the pure product1-but-3-enylcarbamoylmethyl-3-cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole-6-carboxylicacid but-3-enylamide 16-4 as a yellow solid; m/z=646 (M+H⁺).

Step D.

The final compound 17 was synthesized following the procedure reportedin the step E of the synthesis of example 15, starting from 16-4 (0.41g, 0.636 mmol) instead of 15-4 and yielding 0.162 g (41%) of the pureproduct 17; m/z=618 (M+H⁺), NMR (DMSO-d6); δ (ppm) 1.03-1.27 (m, 3H),1.64 (m, 1H), 1.074 (m, 4H), 1.88 (m, 2H), 2.19 (m, 1H), 2.34 (m, 3H),2.61 (m, 1H), 2.64 (s, 3H, Me), 2.72 (s, 3H, Me), 3.24 (m, 2H), 3.39 (m,2H), 4.48+4.51 (s, 2H, 0.3/0.7), 5.36 (m, 1H), 5.54 (m, 1H), 7.44+7.50(d, J=8.4 Hz, 1H, 0.3/0.7), 7.45+7.57 (t, J=5.8 Hz, NH, 0.3/0.7rotamers), 7.73+7.92 (s, 1H, 0.3/0.7), 7.84 (d, J=8.4 Hz, 1H), 7.92 (d,J=8.6 Hz, 1H), 7.92+7.98 (dd, J=1.5 Hz, 8.6 Hz, 1H, 0.3/0.7), 8.10 (d,J=8.6 Hz, 1H), 8.31+8.51 (m, 1H, 0.7/0.3), 8.54 (d, J=8.8 Hz, 1H).

Example 17 Synthesis of17-cyclohexyl-18-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-10,10-dioxo-10λ⁶-thia-1,4,11-triaza-tricyclo[11.5.2.0^(16,19)]icosa-7,13(20),14,16(19),17-pentaene-3,12-dione(18)

Step A.

To a solution of intermediate 16-3 (1.17 g, 2.061 mmol) in THF (100 mL),cooled at 0° C. with an ice bath, was added a solution of LiOH (56%, 107mg, 1.2 eq) in water (6 mL) dropwise. The reaction mixture was stirredat 0° C. until completion (30 h), next acidified to pH 4 with HCl 3 Mand concentrated under reduced pressure. Water was then added to theresidue and the yellow precipitate was filtered off and washed withpetroleum ether, affording 1.09 g (95%) of[1-carboxymethyl-3-cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole]-6-carboxylicacid methyl ester 17-1, which was used without any further purificationin the next step; m/z=554 (M+H⁺).

Step B.

A mixture of the previous intermediate 17-1 (506 mg, 0.915 mmol), HATU(686 mg, 1.97 eq), but-3-enylamine (83 mg, 1.1 eq) and Hunig's base (352mg, 3 eq) in dry DMF (5 mL) was stirred at room temperature under N₂.After 18 h, the reaction mixture was poured into water and theprecipitate was filtered off, washed with water and heptane, affording457 mg (82%) of the desired product1-(3-butenyl-carbamoylmethyl)-3-cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-1H-indole-6-carboxylicacid methyl ester 17-2 as a yellow solid, which was used without anyfurther purification in the next step; m/z=607 (M+H⁺).

Step C.

To a solution of prop-2-ene-1-sulfonyl chloride 17-3 (5 g, 35.56 mmol)in dry THF, at 0° C., was bubbled NH₃ gas during 30 min. The reactionmixture was then concentrated under reduced pressure, ethyl acetate wasadded and the reaction mixture was heated at 70° C., then filtered oversilica (hot) and washed with hot ethyl acetate. The organic layers wereconcentrated and the residue was crystallized from pentane, to give 4 g(93%) of the desired product prop-2-ene-1-sulfonic acid amide 17-4 as awhite solid; m/z=122 (M+H⁺).

Step D.

To a solution of intermediate 17-2 (457 mg, 0.754 mmol) in THF/methanol(1:1, 10 mL) was added a solution of NaOH (3.05 g, 100 eq) in water (5mL) at room temperature. The reaction mixture was stirred at roomtemperature until completion (24 h), then concentrated under reducedpressure, diluted with water and acidified with HCl 6 M until pH 3 witha vigorous stirring. The resulting precipitate was filtered off andwashed with petroleum ether, affording 409 mg (91%) of the desiredintermediate as a yellow solid, which was used without any furtherpurification in the next step; m/z=593 (M+H⁺).

A mixture of the previous intermediate (404 mg, 0.682 mmol), EDCI (224mg, 1.7 eq), 17-4 (167 mg, 2 eq) and DMAP (150 mg, 1.8 eq) in dry DMF(10 mL) was stirred at room temperature under N₂. After 18 h, thereaction mixture was poured into water and the product was extractedwith a mixture of ethyl acetate and THF several times. The organiclayers were combined, washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. Recrystallization fromCH₂Cl₂/diethylether afforded 268 mg (56%) ofN-but-3-enyl-2-[3-cyclohexyl-2-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-6-(prop-2-ene-1-sulfonyl-aminocarbonyl)-indol-1-yl]-acetamide17-5 as a yellow solid; m/z=696 (M+H⁺).

Step E.

A solution of intermediate 17-5 (260 mg, 0.373 mmol) in DCE (400 mL) wasbubbled through with N₂ during 2 h. Hoveyda-Grubbs 1^(st) generationcatalyst (45 mg, 0.2 eq) was next added and the reaction mixture washeated at 80° C. under N₂ overnight. The reaction mixture was thenconcentrated under reduced pressure and purified by flash chromatography(CH₂Cl₂/methanol 95:5) to give the desired product 18 as a gray powderafter recrystallization from CH₂Cl₂/isopropyl ether; m/z=668 (M+H⁺), NMR(DMSO-d6): δ (ppm) 1.20-1.30 (m, 3H), 1.63-1.93 (m, 9H), 2.34 (m, 2H),2.66 (m, 1H), 2.67 (s, 3H), 2.73 (s, 3H), 3.23 (m, 2H), 4.50 (s, 2H),5.64 (m, 2H), 7.45 (m, 1H), 7.73-8.12 (m, 6H), 8.47 (broad s, 1H, NHCO),8.54 (d, J=8.4 Hz, 1H), 11.47 (broad s, 1H, NHSO₂).

Example 18 Synthesis of17-cyclohexyl-18-(2-fluoro-4-(2-(4-methanesulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy)-phenyl)-9-methyl-10,10-dioxo-10λ⁶-thia-1,4,9,11-tetraaza-tricyclo[11.5.2.0^(16,19)]icosa-6,13(20),14,16(19),17-pentaene-3,12-dione(19)

Step A.

The intermediate 18-1 was synthesized following the step E of example11, starting from 11-4 and 14-1 instead of intermediate 3-8, and wasobtained in 68% yield; m/z=775 (M+H)⁺.

Step B

To a solution of intermediate 18-1 (1.19 g, 1.534 mmol) in THF/methanol1:1, cooled at 0° C. with an ice bath, was added a solution of LiOH (40mg, 1.1 eq) in water (6 mL) dropwise. The reaction mixture was stirredat 0° C. during 4 h then at room temperature, concentrated under reducedpressure to remove organic solvents, diluted with water, acidified to pH4 with HCl 3 M and extracted with THF. The organic layer was separated,dried over magnesium sulfate, filtered and concentrated to give 1.04 g(89%) of the target product 18-2 as a yellow foam; m/z=761 (M+H⁺).

Step C

Formic acid (1.626 g, 35.3 mmol) was added to chlorosulfonyl isocyanate18-3 (5 g, 1 eq) in a cooled stirred flask. Dry toluene (12 mL) was thenadded to the reaction mixture and the cooling bath was removed. Thereaction mixture was stirred at room temperature overnight, thenfiltered and the filtrate was concentrated to dryness to afford 4.08 gof the target product 18-4 as a white solid.

Step D

To a solution of N-methylprop-2-en-1-amine (7.53 g, 106 mmol) in THF (55mL) was added sulfamoyl chloride 18-4 (4.08 g, 35.3 mmol) in THF (20 mL)dropwise, at 0° C. After stirring at 0° C. for 1 h, the ice bath wasremoved and the reaction mixture was stirred at room temperature for 3days, then was concentrated under reduced pressure and the crude productwas purified by flash chromatography using dichloromethane/methanol 9:1as eluent to afford 2.64 g (50%) of the desired product 18-5 as a yellowsolid; m/z=151 (M+H⁺).

Step E

Intermediate1-allylcarbamoylmethyl-3-cyclohexyl-2-(2-fluoro-4-(2-(4-methane-sulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy)-phenyl)-1H-indole-6-carboxylicacid methyl ester 18-6 was obtained in 82% yield (351 mg) as a whitepowder, following the procedure reported for the synthesis of compound12-3, using intermediate 18-2 (407 mg, 0.535 mmol) instead ofintermediate 12-2 and allylamine (43 mg) instead of but-3-enylamine;m/z=800 (M+H)⁺.

Step F

Intermediate1-allylcarbamoylmethyl-3-cyclohexyl-2-(2-fluoro-4-(2-(4-methane-sulfonyl-piperazin-1-yl)-5-(2-oxo-pyrrolidin-1-yl)-benzyloxy)-phenyl)-1H-indole-6-carboxylicacid 18-7 was obtained in quantitative yield (351 mg), following theprocedure reported for the synthesis of compound 12-4 and usingintermediate 18-6 (351 mg, 0.439 mmol) instead of intermediate 12-3;m/z=786 (M+H)⁺.

Step G

Intermediate 18-8 was synthesized in 69% yield (200 mg, 0.218 mmol)following the procedure reported for the synthesis of compound 12-5,using intermediate 18-7 instead of intermediate 12-4 and intermediate18-5 instead of prop-2-en-1-sulfonamide; m/z=919 (M+H)⁺.

Step H

The target product 19 was synthesized from intermediate 18-8, followingthe procedure reported for the synthesis of compound 3 and usingHoveyda-Grubbs 2^(nd) generation catalyst instead of the 1^(st)generation catalyst; m/z=891 (M+H)⁺.

Example 19 Synthesis of19-(4-Chloro-phenyl)-18-cyclohexyl-10-methyl-11,11-dioxo-11λ⁶-thia-1,4,10,12-tetraaza-tricyclo[12.5.2.017,20]henicosa-7,14(21),15,17(20),18-pentaene-3,13-dione(20)

Step A

Compound 19-2 was synthesized following the steps E and F used inexample 1, using the bromoindole 19-1 (synthesized as described inUS2007270405 A1) instead of compound 1-5, and 4-chlorophenyl boronicacid instead of 3-furan boronic acid, and was obtained as a whitepowder, m/z=410 (M+H)⁺ (yield 60%).

Step B

Compound 20 was synthesized in a similar way as compound 19, followingthe steps B to H of example 18, with the following modifications:

-   -   in step B, compound 19-2 was used instead of compound 18-1;    -   in step E, But-3-enylamine was used instead of allylamine;    -   in step F, a mixture of TFA and DCM was used instead of lithium        hydroxide.

Compound 20 was obtained as a mixture of E/Z isomers with the ratio14/86, m/z=570 (M+H)⁺. ¹H NMR CDCl₃: 1.25-1.32 (m, 4H), 1.75-1.85 (m,6H), 2.2 (s, 2H), 2.6-2.75 (m, 1H), 3.3 (s, 3H), 3.5 (s, 2H), 3.8 (s,2H), 4.6 (s, 2H), 5.65-5.75 (m, 2H), 6.75 (s, 1H), 7.5-7.55 (m, 4H),7.65-7.75 (m, 2H), 7.8 (d, J=8.44 Hz, 1H), 9.6 (s, 1H).

Example 20 Synthesis of19-(4-Chloro-phenyl)-18-cyclohexyl-10-methyl-11,11-dioxo-11λ⁶-thia-1,4,10,12-tetraaza-tricyclo[12.5.2.017,20]henicosa-14(21),15,17(20),18-tetraene-3,13-dione(21) and18-Cyclohexyl-10-methyl-11,11-dioxo-19-phenyl-11λ⁶-thia-1,4,10,12-tetraaza-tricyclo[12.5.2.017,20]henicosa-14(21),15,17(20),18-tetraene-3,13-dione(22)

Compound (20) (140 mg, 0.246 mmol) was dissolved in ethyl acetate (20mL) and was hydrogenated on Pd/C. The reaction mixture was thenconcentrated and the residue was purified by silica gel flashchromatography (mixture of DCM and ethyl acetate as eluent), then bypreparative HPLC to yield 79 mg of compound (21), m/z=572 (M+H)⁺ ¹H NMRCDCl₃: 1.25-1.32 (m, 4H), 1.4-1.5 (m, 4H), 1.75-1.85 (m, 8H), 2.5-2.6(m, 1H), 3.2 (s, 3H), 3.25-3.3 (m, 4H), 4.6 (s, 2H), 6.25 (t, J=5.84 Hz,1H), 7.3 (d, J=8.24 Hz, 2H), 7.4 (d, J=8.24 Hz, 2H), 7.6 (d, J=8.36 Hz,1H), 7.8 (s, 1H), 7.88 (d, J=8.36 Hz, 1H), 10 (s, 1H), and 10 mg ofcompound (22), m/z=537 (M+H)⁺, ¹H NMR CDCl₃: 1.25-1.32 (m, 4H), 1.4-1.5(m, 4H), 1.75-1.85 (m, 8H), 2.5-2.6 (m, 1H), 3.2 (s, 3H), 3.25-3.3 (m,4H), 4.6 (s, 2H), 6.25-6.3 (m, 1H), 7.3-7.5 (m, 3H), 7.4-7.5 (m, 2H),7.6 (d, J=8.44 Hz, 1H), 7.8 (s, 1H), 7.88 (d, J=8.44 Hz, 1H), 9.7 (s,1H).

Example 21 Synthesis of18-(4-Chloro-phenyl)-17-cyclohexyl-4,9-dimethyl-10,10-dioxo-10λ⁶-thia-1,4,9,11-tetraaza-tricyclo[11.5.2.016,19]icosa-6,13(20),14,16(19),17-pentaene-3,12-dione(23)

Compound 23 was synthesized in a similar way as compound 19, followingthe steps B to H of example 18, with the following modifications:

-   -   in step B, compound 19-2 was used instead of compound 18-1;    -   in step F, a mixture of TFA and DCM was used instead of lithium        hydroxide.

Example 22 Synthesis of18-(4-Chloro-phenyl)-17-cyclohexyl-4,9-dimethyl-10,10-dioxo-10λ⁶-thia-1,4,9,11-tetraaza-tricyclo[11.5.2.016,19]icosa-13(20),14,16(19),17-tetraene-3,12-dione(24)

compound (24) was synthesized following the procedure reported inexample 20 and was obtained in 12% yield, m/z=572 (M+H)⁺.

Example 23 Synthesis of17-Cyclohexyl-18-(4-methoxy-phenyl)-9-methyl-10,10-dioxo-10λ⁶-thia-1,4,9,11-tetraaza-tricyclo[11.5.2.016,19]icosa-13(20),14,16(19),17-tetraene-3,12-dione(25)

Step A

To a stirred solution of the indole derivative 1-5 (5 g, 14.87 mmoles)in a mixture of dioxane/ethanol/water 1/1/1 (75 mL) were added4-methoxyphenyl boronic acid (3.39 g, 1.5 eq), sodium carbonate (4.73 g,3 eq) and Bis(tri-o-tolylphosphine)palladium(II) Dichloride (1.172 g,0.1 eq). The reaction mixture was stirred at 80° C. under nitrogen.After completion, the reaction mixture was concentrated under vacuum,then ethylacetate was added. The resulting precipitate and the filtratewere treated separately. The precipitate was filtered off, redissolvedin hot ethylacetate. After filtration, the organic layer was dried overmagnesium sulfate, filtered and concentrated to give 1.2 g of the targetcompound 23-1. The first filtrate was washed with a sodium bicarbonateaqueous solution, then dried over magnesium sulfate, filtered andconcentrated. The residue was recrystallized from DCM to afford a secondcrop of the target compound 23-1 (3.33 g). In total, 4.53 g (84% yield)of the target compound was obtained, m/z=364 (M+H)⁺.

Step B

To a stirred solution of intermediate 23-1 (3.8 g, 10.46 mmoles) in dryDMF (50 mL) was added sodium hydride (0.502 g, 1.2 eq, 60% in oil).After 5 minutes, bromo-acetic acid tert-butyl ester (2.447 g, 1.2 eq)was added. After 2 h at room temperature, the reaction mixture waspoured into 200 mL of cold water. The resulting precipitate was filteredoff and washed with water, and the aqueous layer was extracted withethylacetate. The organic layer was washed with water, dried overmagnesium sulfate, filtered and concentrated to dryness. This residueand the former precipitate were combined to give 5 g of the targetcompound 23-2, which was used without further purification in thefollowing step, m/z=478 (M+H)⁺.

Step C

To a solution of intermediate 23-2 (5 g, 10.46 mmoles) was addedtrifluoroacetic acid (19.29 mL, 20 eq). After stirring overnight at roomtemperature, the reaction mixture was concentrated to dryness undervacuum. The residue was redissolved in DCM, washed with water, driedover magnesium sulphate, filtered and concentrated to give 4.49 g (82%)of the target compound 23-3, m/z=422 (M+H)⁺.

Step D

A solution of intermediate 23-3 (0.5 g, 1.186 mmole),(4-amino-butyl)-methyl-carbamic acid tert-butyl ester (0.312 g, 1.3 eq),HATU (0.677 g, 1.5 eq) and DIPEA (0.23 g, 1.5 eq) in DCM was stirred atroom temperature. After completion, the reaction mixture was dilutedwith DCM, washed with water, dried over magnesium sulphate, filtered andconcentrated. The crude was purified by silica gel flash chromatography(DCM to DCM/ethylacetate 1/1) to give 0.455 g (64% yield) of the targetproduct 23-4, m/z=606 (M+H)⁺.

Step E

To a solution of compound 23-4 (0.455 g, 0.735 mmoles) was addedtrifluoroacetic acid (0.55 mL, 10 eq). After stirring overnight at roomtemperature, the reaction mixture was concentrated to dryness undervacuum. The residue was redissolved in DCM, washed with a saturatedsodium carbonate aqueous solution then water, dried over magnesiumsulphate, filtered and concentrated to give 0.351 g (94%) of the targetcompound 23-5, m/z=506 (M+H)⁺.

Step F

A mixture of compound 23-5 (0.351 g, 0.694 mmole) and sulfamide (0.200g, 3 eq) in dioxane (7 mL) was heated at 100° C. in a microwave ovenduring 40 minutes. The reaction mixture was then concentrated andredissolved in DCM. The precipitate of sulfamide in excess was filteredoff and the filtrate was concentrated to dryness to give 0.335 g (83%yield) of the target product 23-6, which was used without any furtherpurification in the next step, m/z=585 (M+H)⁺.

Step G

A mixture of methylester 23-6 (0.327 g, 0.559 mmole) and NaOH (2 mL, 50%w/w aqueous solution) in THF was stirred at room temperature overnight.The reaction mixture was then concentrated, acidified with HCl 3N untilpH 0-1 and extracted with DCM. The organic layer was dried overmagnesium sulphate, filtered and concentrated to give 0.28 g (88% yield)of the target product 23-7, m/z=571 (M+H)⁺.

Step H

A solution of compound 23-7 (0.26 g, 0.456 mmole) and CDI (0.222 g, 3eq) in CH₃CN was stirred at room temperature until complete conversionto the acylimidazole compound 23-8. The reaction mixture was thenconcentrated and the residue was purified by flash chromatography(gradient of ethylacetate to CH₃CN) to give 77 mg of 23-8. Thisintermediate was subsequently redissolved in CH₃CN (10 mL) and DBU (41.5mg, 2.2 eq) was added. After 30 minutes at room temperature, acetic acid(2 drops) was added and the reaction mixture was concentrated.Purification by flash chromatography (gradient of ethylacetate toethylacetate/CH3CN 7/3) afforded 16 mg of the target product 25, m/z=553(M+H)⁺. NMR (DMSO-d6): δ (ppm) 1.10-1.46 (5H, m), 1.59-1.82 (5H, m),1.82-2.05 (4H, m), 2.63 (3H, s), 3.00-3.15 (2H, m), 3.15-3.24 (2H, m),3.82 (3H, s), 4.39 (2H, s), 7.09 (2H, d, J=8.6 Hz), 7.39 (2H, d, J=8.6Hz), 7.54 (1H, d, J=8.6 Hz), 7.67 (1H, d, J=8.6 Hz), 7.94 (1H, s), 8.43(1H, s(br))

Example 24 Synthesis of18-Cyclohexyl-19-(4-methoxy-phenyl)-10-methyl-11,11-dioxo-11λ⁶-thia-1,4,10,12-tetraaza-tricyclo[12.5.2.017,20]henicosa-14(21),15,17(20),18-tetraene-3,13-dione(26)

Step A

A solution of compound 23-3 (0.5 g, 1.186 mmole),N-(5-Amino-pentyl)-N-methyl-2-nitro-benzenesulfonamide (0.786 g, 2.2eq), synthesized as described in example 29, HATU (1.128 g, 2.5 eq) andDIPEA (0.537 g, 3.5 eq) in DCM (5 mL) was stirred at room temperature.After completion, the reaction mixture was diluted with DCM, washed withwater, dried over magnesium sulfate, filtered and concentrated. Thecrude was purified by silica gel flash chromatography (gradient ofheptane to DCM to ethylacetate) to give 0.585 g (70% yield) of thetarget product 24-1, m/z=705 (M+H)⁺.

Step B

A mixture of compound 24-1 (0.58 g, 0.823 mmole), cesium carbonate(0.402 g, 1.5 eq) and a PS-thiophenol resin (1.3 eq, 1.4 mmol/g) in THFwas shaken overnight. The resin was then filtered off and more cesiumcarbonate (0.402 g, 1.5 eq) and PS-thiophenol resin (1.3 eq, 1.4 mmol/g)were added. After completion, the reaction mixture was filtered off andthe filtrate was concentrated. The obtained residue was purified by acatch and release method, using a MP-TsOH SPE column, to give 0.3 g (70%yield) of the target product 24-2, m/z=520 (M+H)⁺.

Step C

The target product 24-3 was obtained in 97% yield following theprocedure reported in step F of example 23, using compound 24-2 (0.290g, 0.558 mmole) instead of compound 23-5, m/z=599 (M+H)⁺.

Step D

The target product 24-4 was obtained in 99% yield following theprocedure reported in step G of example 23, using methyl ester 24-3(0.340 g, 0.558 mmole) instead of methyl ester 23-6, m/z=585 (M+H)⁺.

Step E

The target product 26 was obtained in 31% yield following the procedurereported in step H of example 23, using intermediate 24-4 (0.328 g,0.558 mmole) instead of 23-7, m/z=567 (M+H)⁺. ¹H NMR (δ, DMSO-d6):1.10-1.62 (9H, m), 1.62-1.82 (5H, m), 1.82-1.97 (2H, m), 2.75 (3H, s),3.01-3.20 (4H, m), 3.83 (3H, s), 4.42 (2H, s), 7.09 (2H, d, J=8.3 Hz),7.40 (2H, d, J=8.3 Hz), 7.55 (1H, d, J≈8 Hz), 7.70 (1H, d, J≈8 Hz), 7.90(1H, s), 8.36 (1H, s(br))

Example 25 Synthesis of18-Cyclohexyl-19-(4-methoxy-phenyl)-7-methyl-11,11-dioxo-11λ⁶-thia-1,4,7,10,12-pentaaza-tricyclo[12.5.2.017,20]henicosa-14(21),15,17(20),18-tetraene-3,13-dione(27)

Step A

A solution of compound 23-3 (0.5 g, 1.186 mmole),N1-(2-Amino-ethyl)-N-1-methyl-ethane-1,2-diamine (0.695 g, 5 eq), HATU(0.677 g, 1.5 eq) and DIPEA (0.23 g, 1.5 eq) in DCM (5 mL) was stirredat room temperature. After 2 days at room temperature, the reactionmixture was diluted with DCM, washed with water, dried over magnesiumsulphate, filtered and concentrated. The crude was purified by silicagel flash chromatography (gradient of ethylacetate to ethylacetate/NH₃in MeOH 8/2) to give 0.120 g (19% yield) of the target product 25-1,m/z=521 (M+H)⁺.

Step B

The target product 25-2 was obtained in 49% yield following theprocedure reported in step F of example 23, using compound 25-1 (0.240g, 0.461 mmole) instead of compound 23-5, m/z=600 (M+H)⁺.

Step C

The target product 25-3 was obtained in 21% yield following theprocedure reported in step G of example 23, using methyl ester 25-2(0.060 g, 0.1 mmol) instead of methyl ester 23-6, m/z=586 (M+H)⁺.

Step D

The target product (27) was obtained in 11% yield following theprocedure reported in step H of example 23, using intermediate 25-3instead of 23-7, m/z=568 (M+H)⁺. ¹H NMR (δ, DMSO-d6): 1.10-1.40 (4H, m),1.54-1.82 (6H, m), 1.83-1.99 (2H, m), 2.19 (3H, s), 2.61-2.70 (2H, m),2.96-3.10 (2H, m), 3.10-3.22 (2H, m), 3.57 (1H, s), 3.83 (3H, s), 4.40(2H, s), 4.99-5.13 (1H, m), 7.08 (2H, d, J=8.1 Hz), 7.39 (2H, d, J=8.1Hz), 7.53 (1H, d, J=8.1 Hz), 7.64 (1H, d, J=8.1 Hz), 7.96 (1H, s),8.46-8.60 (1H, m)

Example 26 Synthesis of17-Cyclohexyl-18-furan-3-yl-9-methyl-10,10-dioxo-10λ⁶-thia-1,4,9,11-tetraaza-tricyclo[11.5.2.016,19]icosa-13(20),14,16(19),17-tetraene-3,12-dione(28)

Step A

The target compound 26-1 was obtained in 82% yield following theprocedure reported in step A of example 12, using intermediate 1-7instead of 10-9, m/z=382 (M+H)⁺.

Step B

The target compound 26-2 was obtained following the procedure reportedin step D of example 23, using intermediate 26-1 instead of intermediate23-3, m/z=566 (M+H)⁺.

Step C

The target compound 26-3 was obtained following the procedures reportedin steps E, F and G of example 23, using intermediate 26-2 instead ofintermediate 23-4, m/z=531 (M+H)⁺.

Step D

The target product (28) was obtained in 9% yield following the procedurereported in step H of example 23, using intermediate 26-3 instead of23-7, m/z=513 (M+H)⁺. ¹H NMR, DMSO-d₆: δ 1.42-1.21 (m, 5H), 1.82-1.62(m, 5H), 2.00-1.81 (m, 4H), 2.58 (s, 3H), 2.73-2.62 (m, 1H), 3.08 (t,J=7.5 Hz, 2H), 3.25-3.17 (m, 2H), 4.53 (s, 2H), 6.67 (s, 1H), 7.59 (d,8.25 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.86 (s, 2H), 8.00 (s, 1H), 8.32(s, 1H), 8.55 (br s, 1H)

Example 27 Synthesis of18-Cyclohexyl-19-furan-3-yl-10-methyl-11,11-dioxo-11λ⁶-thia-1,4,10,12-tetraaza-tricyclo[12.5.2.017,20]henicosa-7,14(21),15,17(20),18-pentaene-3,13-dione(29)

The target product (29) was synthesized in a similar way as compound 19,following the steps B to H of example 18, with the followingmodifications:

-   -   in step B, intermediate 1-7 was used instead of compound 18-1    -   in step E, but-3-enylamine was used instead of allylamine

Compound (29) was obtained as a mixture of E/Z isomers, m/z=525 (M+H)⁺.

Example 28 Synthesis of18-Cyclohexyl-19-furan-3-yl-10-methyl-11,11-dioxo-11λ⁶-thia-1,4,10,12-tetraaza-tricyclo[12.5.2.017,20]henicosa-14(21),15,17(20),18-tetraene-3,13-dione(30)

The target product (30) was obtained in 81% yield following theprocedure reported in example 20, m/z=527 (M+H)⁺.

Example 29 Synthesis ofN-(5-amino-pentyl)-N-methyl-2-nitro-benzenesulfonamide (31)

Step A

To a solution of (5-amino-pentyl)-carbamic acid tert-butyl ester (1 g,4.94 mmol) in DCM (10 mL) were added 2-nitrobenzene sulfonyl chloride(1.15 g, 1.05 eq) and DIPEA (0.958 g, 1.5 eq) at room temperature. After1 h, the reaction mixture was diluted with water, washed with a solutionof aqueous citric acid, dried over magnesium sulphate, filtered andconcentrated to give 1.91 g (quantitative yield) of the target product29-1, which was used without any further purification in the next step,m/z=388 (M+H)⁺.

Step B

To a solution of intermediate 29-1 (1.91 g, 4.92 mmol) and potassiumcarbonate (0.816 g, 1.2 eq) in acetone (10 mL) was added methyl iodide(0.733 g, 1.05 eq) at room temperature. After completion, the reactionmixture was diluted with water and extracted with DCM. The organic layerwas dried over magnesium sulfate, filtered and concentrated.Purification by flash chromatography on silica gel (eluent: DCM)afforded 1.29 g (65% yield) of the target product 29-2, m/z=402 (M+H)⁺.

Step C

The target product 31 was obtained in a quantitative yield following theprocedure reported in step E of example 23, using intermediate 29-2(1.29 g, 3.21 mmoles) instead of intermediate 23-4, m/z=302 (M+H)⁺.

Example 30 Activity of Compounds of Formula (I)

a) Protein Purification

The cDNA encoding NS5B amino acid 1-570 (HC-J4, genotype 1b, pCV-J4L6S,genebank accession number AF054247) was subcloned into the Nhe I and XhoI restriction sites of pET-21b. Expression of the subsequent His-taggedC-terminal 21 amino acid deleted NS5B was performed as follows:

The NS5B expression construct was transformed into E. coli BL21(DE3)(Novagen, Madison, Wis.). Five milliliters of LB-medium supplementedwith ampicillin (50 μg/mL) was inoculated with one colony. When thepre-culture reached an optical density of 0.6 measured at 600 nm, it wastransferred to fresh LB-medium supplemented with ampicillin, at a ratioof 1:200. Cells were grown to an optical density at 600 nm of 0.6, afterwhich the expression cultures were shifted to a growth temperature of20° C. following induction with ispopropyl-1-thio-β-D-galactopyranosideand MgCl₂ at a final concentration of 0.4 mM and 10 μM, respectively.After ten hours of induction, cells were harvested by centrifugation andresuspended in 20 mM Tris-HCl, pH 7.5, 300 mM NaCl, 10% glycerol, 0.1%NP40, 4 mM MgCl₂, 5 mM DTT supplemented with EDTA-free Complete ProteaseInhibitor (Roche, Basel, Switzerland). Cell suspensions were disruptedby sonication and incubated with 10-15 mg/L of DNase I (Roche, Basel,Switzerland) for 30 minutes. Cell debris was removed throughultracentrifugation at 30,000×g for 1 hour and clarified cell lysate wasflash frozen and stored at −80° C. prior to purification.

Clarified cell lysate was thawed and subsequently loaded onto a 5 mLpre-packed HisTrap FF column equilibrated with 25 mM HEPES, pH 7.5, 500mM NaCl, 10% glycerol and 5 mM DTT. Proteins were eluted with 500 mMimidazole at a flow rate of 1 mL/min. Fractions containing the proteinof interest were applied onto a pre-packed 26/10 HiPrep Desalting Columnequilibrated with 25 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol and 5mM DTT. The buffer-exchanged NS5B peak was then applied onto a 20 mLPoly-U Sepharose column. Protein was eluted with an increasing saltgradient and fractions collected. Protein purity was assessed on Nu-PAGEpre-cast gels (Invitrogen, Carlsbad, Calif.). Purified NS5B samples wereconcentrated using Centri-Prep concentrators (Millipore, Billerica,Mass., USA) and protein concentrations were determined by Bradford assay(Pierce, Rockford, Ill., USA).

b) Protein Sequence

PDB: 1nb4, Apo form

The protein sequence is as described in WO 2007/026024. Calc. Mol.Properties 64941.4 g/mol

c) Inhibition Assay

Measurement of HCV NS5B polymerization activity was performed byevaluating the amount of radiolabeled GTP incorporated by the enzyme ina newly synthesized RNA using heteropolymeric RNA template/primer. Thehigh-throughput RNA dependent RNA polymerase (RdRp) assay was carriedout in 384-well plates using 100 nM enzyme, 300 nM 5′-biotinylatedoligo(rG₁₃)/poly(rC) primer-template, 600 nM of GTP, and 0.1 μCi of[³H]GTP in 25 mM Tris-HCl, pH 7.5, 5 mM MgCl₂, 25 mM KCl, 17 mM NaCl and3 mM of dithiothreitol (DTT). Test compounds were dissolved in DMSO. Thetest compounds were added to the preformed polymerase-template complex,and incubated at room temperature for 15 min before the addition ofnucleoside triphosphates (NTP). The 30 μl reaction was terminated after2 h at 25° C. upon addition of 30 μl PVT-SPA beads (Amersham BiosciencesRPNQ0009, 5 mg/ml in 0.5 M EDTA). After incubation at 25° C. for 30 min,the plate was counted using a Packard TopCount microplate reader (30sec/well, 1 min count delay) and IC₅₀ values were calculated.

d) Replicon Assay

The compounds of formula (I) were examined for activity in theinhibition of HCV RNA replication in a cellular assay. The assaydemonstrated that the compounds of formula (I) exhibited activityagainst HCV replicons functional in a cell culture. The cellular assaywas based on a bicistronic expression construct, as described by Lohmannet al. (1999) Science vol. 285 pp. 110-113 with modifications describedby Krieger et al. (2001) Journal of Virology 75: 4614-4624, in amulti-target screening strategy. In essence, the method was as follows.

The assay utilized the stably transfected cell line Huh-7 luc/neo(hereafter referred to as Huh-Luc). This cell line harbors an RNAencoding a bicistronic expression construct comprising the wild typeNS3-NS5B regions of HCV type 1b translated from an Internal RibosomeEntry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by areporter portion (firefly luciferase), and a selectable marker portion(neo^(R), neomycine phosphotransferase). The construct is bordered by 5′and 3′ NTRs (non-translated regions) from HCV type 1b. Continued cultureof the replicon cells in the presence of G418 (neo^(R)) is dependent onthe replication of the HCV RNA. The stably transfected replicon cellsthat express HCV RNA, which replicates autonomously and to high levels,encoding inter alia luciferase, were used for screening the antiviralcompounds.

The replicon cells were plated in 384 well plates in the presence of thetest and control compounds which were added in various concentrations.Following an incubation of three days, HCV replication was measured byassaying luciferase activity (using standard luciferase assay substratesand reagents and a Perkin Elmer ViewLux™ ultraHTS microplate imager).Replicon cells in the control cultures have high luciferase expressionin the absence of any inhibitor. The inhibitory activity of the compoundon luciferase activity was monitored on the Huh-Luc cells, enabling adose-response curve for each test compound. EC₅₀ values were thencalculated, which value represents the amount of the compound requiredto decrease the level of detected luciferase activity by 50%, or morespecifically, the ability of the genetically linked HCV replicon RNA toreplicate.

TABLE 1 The following Table 1 lists compounds that were preparedaccording to any one of the above examples. The activities of thecompounds tested are depicted in Table 3.

Cpd. Y A═B R⁴  1 CH₂ CH═CH

 2 CH₂ CH₂—CH₂

 3 CH₂ CH═CH

 4 CH₂ CH═CH

 5 CH₂ CH═CH

 8 CH₂ CH₂—CH₂

 9 CH₂ CH₂—CH₂

10 CH₂ CH₂—CH₂

11 CH₂ CH═CH

12 CH₂ CH═CH

13 SO₂ CH═CH

14 SO₂ CH═CH

15 CH₂ CH═CH

16 CH₂ CH═CH

17 CH₂ CH═CH

18 SO₂ CH═CH

TABLE 2 The following Table 2 lists compounds that were preparedaccording to any one of the above examples. The activities of thecompounds tested are depicted in Table 3. Cpd Structure 19

20

21

22

23

24

Cpd 25

26

27

28

29

30

TABLE 3 The following Table 3 lists the activities of the testedcompounds. IC₅₀ (μM) EC₅₀ (μM) Enzymatic Replicon Cpd assay assay 1 2.23.4 2 9.5 4.3 3 1.1 0.72 4 0.27 0.24 5 0.29 0.58 8 2.79 >32 9 13.0 4.810 6.9 >32 11 0.45 0.69 12 0.36 0.27 13 0.04 2.36 14 0.88 2.04 15 1.580.27 16 1.44 17.61 17 2.70 5.39 18 0.04 12.85 19 0.042 2.36 20 0.17 0.6121 0.19 0.59 22 — 0.43 23 0.45 1.08 24 0.44 0.53 25 0.18 1.76 26 0.190.35 27 0.44 3.47 28 0.11 1.58 29 0.051 0.65 30 0.11 0.79

The invention claimed is:
 1. A compound having the formula (I) or anN-oxide, stereoisomer, tautomer, racemic or salt thereof, wherein

R¹ is a bivalent chain selected from

wherein the sulfonyl group is attached to the remainder of the moleculevia the nitrogen atom of the amide group, and the carbon atom of theacetamide moiety is attached to the remainder of the molecule via thenitrogen of the indole ring of the compound of formula (I); X isselected from —CR^(5a)R^(5b)— or —NR^(5a)—; each of g and h is,independently, an integer selected from 0, 1, 2, 3, 4, or 5, with theproviso that the macrocycle formed by the bivalent chain R¹, the—C(═O)—NH— moiety to which R¹ is attached and the nitrogen and carbonatoms N1, C6, C7, and C7′ of the indole ring, has from 14 to 17 memberatoms; each parallel dashed line (represented by

) represents an optional double bond; R² is hydrogen or C₁₋₆alkyl; R³ isC₃₋₇cycloalkyl; R⁴ is a group selected from:

R^(5a) and R^(5b) are each independently selected from hydrogen;C₁₋₆alkyl; or haloC₁₋₆alkyl; n is 0, 1, or 2; R⁶ is selected fromhydrogen, halo, C₁₋₆alkyl, or C₃₋₇cycloalkyl; R^(6a) is selected fromhydrogen, halo, C₁₋₆alkyl, or C₃₋₇cycloalkyl; R⁷ is phenyl or thiazolyl,wherein each phenyl is optionally substituted with one, two, or threesubstituents, wherein each thiazolyl is optionally substituted with oneor two substituents; wherein the substituents on both phenyl andthiazolyl are each independently selected from halo; cyano; nitro;C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²; —C(═O)R¹³; —C(═O)NR^(9a)R^(9b);—NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³; —NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b);—SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b); phenyl optionally substituted withone, two or three substituents each independently selected from halo,trifluoromethyl, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b);and Het optionally substituted with one or two substituents eachindependently selected from oxo, C₁₋₆alkylsulfonyl, and C₁₋₆alkyl; R⁸ ishydrogen, phenyl, or thiazolyl, wherein each phenyl is optionallysubstituted with one, two, or three substituents, wherein each thiazolylis optionally substituted with one or two substituents; wherein thesubstituents on both phenyl and thiazolyl are each independentlyselected from halo; cyano; nitro; C₁₋₆alkyl; —OR¹²; —C(═O)OR¹²;—C(═O)R¹³; —C(═O)NR^(9a)R^(9b); —NR^(9a)R^(9b); —NR^(9a)C(═O)R¹³;—NR^(9a)C(═O)—CH₂—NR^(9a)R^(9b); —SR¹⁰; —SO₂R¹¹; —SO₂NR^(9a)R^(9b);phenyl optionally substituted with one, two or three substituents eachindependently selected from halo, trifluoromethyl, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, and —C(═O)NR^(9a)R^(9b); and Het optionally substituted withone or two substituents each independently selected from oxo,C₁₋₆alkylsulfonyl, and C₁₋₆alkyl; R^(9a) and R^(9b) are eachindependently selected from hydrogen, C₁₋₆alkyl, or arylC₁₋₆alkyl; orR^(9a) and R^(9b), together with the nitrogen to which they areattached, form a saturated, partially unsaturated, or completelyunsaturated 5-8 membered monocycle, wherein said monocycle optionallycontains one additional heteroatom selected from the group consisting ofoxygen, sulfur and nitrogen, and wherein the remaining monocycle membersare carbon atoms; wherein said monocycle is optionally substituted onany carbon atom with one or two substituents each independently selectedfrom halo, C₁₋₆alkyl, hydroxy, or oxo, wherein aryl is phenyl ornaphthyl; R¹⁰ is C₁₋₆alkyl or C₃₋₇cycloalkyl; R¹¹ is C₁₋₆alkyl orC₃₋₇cycloalkyl; R¹² is hydrogen, C₁₋₆alkyl, or benzyl; R¹³ is C₁₋₆alkyl;Het is pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.
 2. Acompound as claimed in claim 1 wherein R¹ is

wherein the carbon atom carrying the R^(5a) and R^(5b) substituents (theleft side of the depicted R¹ chains) is attached to the remainder of themolecule via the nitrogen atom of the amide group, and the carbon atomof the acetamide moiety (the right side of the depicted R¹ chains) isattached to the remainder of the molecule via the nitrogen of the indolering of the compound of formula (I); each parallel dashed line(represented by

) represents an optional double bond; and R⁴ is a group selected from:


3. A compound according to claim 1, having the structural formula

wherein the parallel dashed line, g, h, R³, R⁶, R⁷, X, n, and R⁸, havethe same meaning as that defined in claim
 1. 4. A compound according toclaim 1 wherein R⁴ is


5. A compound according to claim 1, wherein R⁴ is


6. A compound according to claim 1, wherein R¹ is


7. A compound according to claim 1, wherein each of g and h is,independently, 0, 1, 2, or 3, with the proviso that the macrocycleformed by the bivalent chain R¹, the —C(═O)—NH— moiety to which R¹ isattached and the nitrogen and carbon atoms N1, C6, C7, and C7′ of theindole ring, has from 14 to 16 member atoms.
 8. A compound according toclaim 1, wherein R² is hydrogen or C₁₋₄alkyl.
 9. A pharmaceuticalcomposition comprising an anti-virally effective amount of a compound asclaimed in claim 1 and a pharmaceutically acceptable carrier.